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Clozapine (CLZ) -related accidents or crimes are common in the world. Oral fluid drug detection is a convenient measure of dealing with things like that. There has not been any literature reported detailedly the representation rule of clozapine and its metabolites in oral fluid so far. The study aimed to describe the pharmacokinetics of CLZ and its metabolites N-desmethylclozapine and clozapine-N-oxide in human oral fluid after a single 12.5 mg oral dose of CLZ. Twenty-nine volunteers, including 20 males and 9 females, were recruited, and 2 mL oral fluid was collected from each participant at post-consumption time-points of prior (zero), 0.5, 1.5, 3, 5, 8, 12, 24, 36, 51, 82, and 130 h, respectively. Analytes of interest were extracted with solid-phase extraction and analyzed with liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters were calculated using the pharmacokinetic software DAS according to the non-compartment model. The maximum concentration, the time of maximum concentration, oral clearance, and the elimination half-life of clozapine were 16.57 ± 9.63 ng/mL, 4.53 ± 3.61 h, 57.65 ± 23.77 L/h and 53.58 ± 52.28 h, respectively. The maximum concentration, the time of maximum concentration, and the elimination half-life of the metabolite N-desmethylclozapine were 3.08 ± 1.19 ng/mL, 9.38 ± 9.33 h and 62.67 ± 82.57 h, respectively; of clozapine-N-oxide were 1.15 ± 0.36 ng/mL, 4.53 ± 2.19 h and 19.15 ± 23.11 h, respectively. It was the first study on the pharmacokinetics of CLZ and its metabolites in the oral fluid of Chinese healthy volunteers, and it provided a basis for the therapeutic drug monitoring and toxicological interpretation in clozapine-related cases. [ABSTRACT FROM AUTHOR]

Risperidone extended‐release injectable suspension (R‐ERIS; marketed as RYKINDO) is a novel immediate‐release version of risperidone formulated as extended‐release microspheres for biweekly intramuscular injection to treat schizophrenia in adults. The pharmacokinetics (PK) and safety of R‐ERIS were evaluated in a multicenter, randomized, open‐label, multiple‐dose study in patients with stable schizophrenia or schizoaffective disorder. Eligible patients (N = 108) 18 to 65 years old were randomized (1:1) to receive IM injections of R‐ERIS 25 mg or the comparator, a biweekly risperidone long‐acting injectable (BW‐RLAI; marketed as RISPERDAL CONSTA) 25 mg for a total of 5 injections. The primary objective was to evaluate the relative bioavailability of active moiety (risperidone plus 9‐hydroxyrisperidone) at steady state. Blood samples were analyzed for risperidone and 9‐hydroxyrisperidone using a validated, specific, and sensitive liquid chromatography with tandem mass spectrometry method. Plasma concentration–time data were analyzed using non‐compartmental methods. Pharmacokinetic parameters were calculated based on individual patient PK profiles. Safety was assessed using standard measures. At steady state, mean plasma concentrations of the active moiety were similar for R‐ERIS and BW‐RLAI. R‐ERIS rapidly released risperidone after the injection without apparent lag time. Plasma active moiety levels reached steady state after the second injection of R‐ERIS. The elimination of the drug was completed approximately 2 weeks earlier for R‐ERIS as compared to that for BW‐RLAI. R‐ERIS was safe and well tolerated. Overall, R‐ERIS exhibited a faster onset and offset than BW‐RLAI and statistical analysis of exposure parameters demonstrated bioequivalence at steady state. [ABSTRACT FROM AUTHOR]

Ivacaftor is the first potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) protein approved for use alone in the treatment of cystic fibrosis (CF). Ivacaftor is primarily metabolized by CYP3A4 and therefore may interact with drugs that are CYP3A4 substrates, resulting in changes in plasma exposure to ivacaftor. The study determined the levels of ivacaftor and its active metabolite M1 by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). We screened 79 drugs and 19 severely inhibited ivacaftor metabolism, particularly two cardiovascular drugs (nisoldipine and nimodipine). In rat liver microsomes (RLM) and human liver microsomes (HLM), the half-maximal inhibitory concentrations (IC50) of nisoldipine on ivacaftor metabolism were 6.55 μM and 9.10 μM, respectively, and the inhibitory mechanism of nisoldipine on ivacaftor metabolism was mixed inhibition; the IC50 of nimodipine on ivacaftor metabolism in RLM and HLM were 4.57 μM and 7.15 μM, respectively, and the inhibitory mechanism of nimodipine on ivacaftor was competitive inhibition. In pharmacokinetic experiments in rats, it was observed that both nisoldipine and nimodipine significantly altered the pharmacokinetic parameters of ivacaftor, such as AUC(0-t) and CLz/F. However, this difference may not be clinically relevant. In conclusion, this paper presented the results of studies investigating the interaction between these drugs and ivacaftor in vitro and in vivo. The objective is to provide a rationale for the safety of ivacaftor in combination with other drugs. [ABSTRACT FROM AUTHOR]

Background: To evaluate the clearance of edoxaban during modeled in vitro continuous renal replacement therapy (CRRT), assess protein binding and circuit adsorption, and provide initial dosing recommendations. Methods: Edoxaban was added to the CRRT circuit and serial pre-filter bovine blood samples were collected along with post-filter blood and effluent samples. All experiments were performed in duplicate using continuous veno-venous hemofiltration (CVVH) and hemodialysis (CVVHD) modes, with varying filter types, flow rates, and point of CVVH replacement fluid dilution. Concentrations of edoxaban and urea were quantified via liquid chromatography-tandem mass spectrometry. Plasma pharmacokinetic parameters for edoxaban were estimated via noncompartmental analysis. Two and three-way analysis of variance (ANOVA) models were built to assess the effects of mode, filter type, flow rate, and point of dilution on CLCRRT. Linear regression was utilized to provide dosing estimations across CRRT effluent flow rates from 0.5 to 5 L/h. Optimal edoxaban doses were suggested using CLCRRT and population non-renal clearance (CLNR) to estimate total clearance and match the systemic AUC associated with efficacy in the treatment of venous thromboembolism. Results: Edoxaban clearance from the CRRT circuit occurred primarily via hemofilter adsorption to the HF1400 and M150 filters at 74% and 65%, respectively, while mean percent protein binding was 41%. Multivariate analyses confirmed the lack of influence of CRRT mode, filter type, and point of dilution on the CLCRRT of edoxaban allowing dosing recommendations to be made based on effluent flow rate. Edoxaban doses of 30-45 mg once daily were estimated to achieve target the AUC threshold for flow rates from 0.5 to 5 L/h. Conclusion: For CRRT flow rates most employed in clinical practice, an edoxaban dose of 45 mg once daily is predicted to achieve target systemic exposure thresholds for venous thromboembolism treatment. The safety and efficacy of this proposed dosing warrants further investigation in clinical studies. [ABSTRACT FROM AUTHOR]

In this study, the mass balance, pharmacokinetics (PK) and metabolism of atuliflapon, a novel 5‐lipoxygenase‐activating protein inhibitor, were investigated in healthy male subjects. A single oral dose of 200 mg [14C]atuliflapon suspension was administered to six healthy male subjects. Mass balance, PK and metabolite profiles of atuliflapon were analyzed using radioactivity monitoring and liquid chromatography with mass spectrometry analysis. The safety of atuliflapon was assessed during the study. Atuliflapon was rapidly absorbed with a median tmax of 1.5 h, followed by a biphasic decline in plasma exposure rendering a terminal half‐life of ~20 h. Unchanged atuliflapon was the predominant radioactive component in plasma, accounting for 40.1% of the total drug‐related exposure (DRE), while a direct N‐glucuronide was the only metabolite exceeding 10% of DRE, accounting for 20.9%. Renal excretion of intact atuliflapon accounted for <1% of the administered dose. In total 85.2% of administered radioactivity was recovered over 312 h with 79.3% and 5.9% in feces and urine, respectively. Parent atuliflapon contributed to approximately 40% of the recovered dose in excreta, while metabolites resulting from phase 1 oxidative pathways accounted for more than 30% of the excreted dose. Overall, a single oral dose of 200 mg [14C]atuliflapon suspension was well tolerated in healthy male subjects. The human metabolism and disposition data obtained will support future development and submissions of atuliflapon as a potential candidate drug for the treatment of cardiovascular, cardiorenal, and respiratory indications. [ABSTRACT FROM AUTHOR]

This study was conducted as a single‐site, open‐label, randomized, replicated crossover trial with 4 treatment periods. The aim was to evaluate the bioequivalence of a generic test drug containing velpatasvir and sofosbuvir compared to an established brand‐name medication in healthy White subjects under fasting conditions. Blood samples were collected at specified intervals up to 72 hours after dosing to measure the concentrations of velpatasvir and sofosbuvir using a certified high‐performance liquid chromatography with tandem mass spectrometry method. The bioequivalence of the 2 formulations was confirmed when statistical analysis showed that confidence intervals for the log‐transformed peak concentration and area under the concentration‐time curve from time 0 to the last quantifiable sample were within an acceptable range from 80% to 125%. Criteria for bioequivalence were met for both area under the concentration‐time curve from time 0 until the last quantifiable sample and peak concentration parameters. No adverse effects were reported during this trial in both groups. [ABSTRACT FROM AUTHOR]

Purpose: Proteinuria can cause interindividual variability in the pharmacokinetics of therapeutic antibodies and may affect therapeutic efficacy. Here, we measured the serum and urinary concentrations of bevacizumab (BV) and nivolumab (NIVO) in patients with proteinuria and reported a case series of these patients. Methods: Thirty-two cancer patients who received BV every 3 weeks or NIVO every 2 weeks between November 2020 and September 2021 at Kyoto University Hospital were enrolled in this study. The serum and urinary concentrations of BV and NIVO were measured using liquid chromatography-tandem mass spectrometry. Results: We divided the BV-treated patients and the NIVO-treated patients into two groups based on the urine protein-creatinine ratio (UPCR): UPCR 1 g/g or higher (BV, n = 9; NIVO, n = 3) and UPCR less than 1 g/g (BV, n = 14; NIVO, n = 6). Serum concentrations of the therapeutic antibodies adjusted by their doses were significantly lower in both BV- and NIVO-treated patients with UPCR 1 g/g or higher compared to those with less than 1 g/g. In patients with UPCR 1 g/g or higher, urinary concentrations of the therapeutic antibodies adjusted by their serum concentrations and urinary creatinine concentrations tended to increase. Conclusion: This case-series study suggests a possibility of reduction in serum concentrations of BV and NIVO in patients with proteinuria by urinary excretion of these drugs. [ABSTRACT FROM AUTHOR]

The novel antimalarial ganaplacide combined with lumefantrine solid dispersion formulation (LUM‐SDF) was effective and well tolerated in the treatment of uncomplicated falciparum malaria in adults, adolescents, and children in a multinational, prospective, randomized, active‐controlled Phase II study conducted between August 2017 and June 2021 (EudraCT 2020‐003284‐25, Clinicaltrials.gov NCT03167242). Pharmacokinetic data from that study are reported here.The trial comprised three parts: a run‐in part in 12 adult/adolescent patients treated with a single dose of ganaplacide 200 mg plus LUM‐SDF 960 mg assessed potential pharmacokinetic (PK) interactions between ganaplacide and lumefantrine; in Part A, adult/adolescent patients received one of the six ganaplacide‐LUM‐SDF regimens or artemether‐lumefantrine; and in Part B, three dose regimens identified in Part A, and artemether‐lumefantrine, were assessed in children aged 2 to <12 years, with body weight ≥10 kg. A rich blood sampling schedule was used for all 12 patients in the PK run‐in part and a subset of patients (N = 32) in Part A, with sparse sampling for remaining patients in Parts A (N = 275) and B (N = 159). Drug concentrations were determined by a validated protein precipitation and reverse phase liquid chromatography with tandem mass spectrometry detection method. Parameters including AUCinf, AUClast, AUC0–t, Cmax, and tmax were reported where possible, using non‐compartmental analysis.In the PK run‐in part, there was no notable increase in ganaplacide or lumefantrine exposure when co‐administered. In Parts A and B, ganaplacide exposures increased with dose, but lumefantrine exposure was numerically under dose‐proportional. Lumefantrine exposure was higher with ganaplacide‐LUM‐SDF than with artemether‐lumefantrine, although high variability was observed. Ganaplacide and lumefantrine exposures (Cmax and AUC0–24 h) were comparable across age and body weight groups. Drug exposures needed for efficacy were achieved using the dose regimen 400 mg ganaplacide plus lumefantrine 960 mg once daily for 3 days under fasted conditions. [ABSTRACT FROM AUTHOR]

The objective of this study was to compare the plasma (PL) and seminal plasma (SP) pharmacokinetic profile of ceftiofur (CEFT) and desuroylceftiofur acetamide (DFCA) after administration of CEFT crystalline-free acid (CCFA) by SC route in two sites of the ear in beef bulls. Four clinically healthy Hereford bulls received a comprehensive physical exam and subsequently a breeding-soundness examination, CBC, and chemistry profile panel. All bulls were diagnosed healthy and satisfactory potential breeders. In one group (n = 2), a single dose of CCFA was administered SC route at the base of the ear (BOE) at a dose of 6.6 mg/kg of body weight. The second group (n = 2) was also administered by SC route in the middle third of the posterior aspect of the ear (MTE). The concentrations of CEFT and DFCA in PL and SP were determined by a high-performance liquid chromatography mass spectrometry (HPLC-MS). Blood and semen samples were collected before the administration of CCFA and at 12, 24, 36, 48, 72, 96, 120, 144, and 168 h after injection. No levels of CEFT were detected in PL and only in 20 of the 40 SP samples (P = 0.0001). The mean level of CEFT in SP was 0.11 % in comparison with the DFCA level. DFCA was found in all PL and SP samples. Therefore, DFCA was chosen to be utilized in the study of the pharmacokinetics parameters both in PL and SP. There were no differences in the mean PL levels of DFCA for the two sites of SC administration between the BOE (102.9 ± 78.9 ng/mL; X ± SD) and to MTE (116.1 ± 70.2 ng/mL; P = 0.58). The mean SP levels of DFCA after administration in the BOE was 857 ± 747 ng/mL, and for the MTE was 549 ± 488 ng/mL without differences between both sites (P = 0.15). The mean level of DFCA in PL was 109.5 ± 74.0 ng/mL, which was lower than the mean SP levels of 695 ± 103 ng/mL (P = 0.001). Moreover, the PL peak DFCA concentration (C max) was 229 ± 46 ng/mL at 36.0 ± 29.4 h (T max) post-administration. The SP C max was 1851 ± 533 ng/mL at 30.0 ± 28.6 h (T max) post-administration. The C max between PL and SP were distinctive (P = 0.004) without any differences in T max between PL and SP (P = 0.60). The terminal half-life for PL DFCA (47.4 ± 29.3 h) was not different than in SP (53.1 ± 23.6 h; P = 0.77). The PL area under the curve concentration time from the first to the last sample (AUC 0–last) was 18,984 ± 4841 ng/mL/h, which was significatively smaller compared with 125,677 ± 59,445 ng/mL/h for SP AUC 0–last (P = 0.04). The PL mean residence time from the first to the last sample (MRT 0–last) was 69.7 ± 15.1 h, and it was similar than for SP of 66.5 ± 7.7 h (P = 0.69). From the present investigation, based in its pharmacokinetic features, it was concluded that CCFA should be an appropriate antibiotic that could be used for the treatment of bull genital infections when its indication is properly outlined. To study the pharmacokinetics of CCFA in SP, DFCA metabolite was appropriated. [ABSTRACT FROM AUTHOR]

Vepdegestrant (formerly ARV-471), a novel proteolysis-targeting chimera (PROTAC), targets estrogen receptor alpha (ERα) for degradation, offering a promising option to treat advanced ER-positive breast cancer. We developed and validated a sensitive and rapid liquid chromatography–tandem mass spectrometry method to quantify vepdegestrant in rodent plasma using bavdegalutamide (formerly ARV-110) as an internal standard. Plasma samples were prepared with protein precipitation using acetonitrile and analyzed using reverse-phase C18 columns and a mobile phase of 10 mM ammonium formate in distilled water and acetonitrile. The method demonstrated linearity from 1 to 1000 ng/mL in mouse and rat plasma, meeting all validation criteria, and successfully applied to in vivo and in vitro studies. Pharmacokinetic analysis revealed low-to-moderate clearance (313.3, 1053 mL/h/kg) and oral bioavailability (17.91, 24.12%) of vepdegestrant in mice and rats, respectively. It was unstable in buffer solutions across pH 2–10 and in phosphate-buffered saline (pH 7.4), likely due to adsorption, but remained stable in mouse and rat plasma at varying temperatures. In liver microsomes, vepdegestrant exhibited moderate stability in rats but was stable in mice, dogs, and humans. These findings enhance the understanding of pharmacokinetic properties of vepdegestrant supporting further development of PROTAC drugs. [ABSTRACT FROM AUTHOR]

Objectives Temocillin, a carbapenem-sparing β-lactam antibiotic, is commonly used at the standard 4 g/day dosage for treating complicated urinary tract infections (cUTIs). However, pharmacokinetic/pharmacodynamic (PK/PD) data supporting this regimen is limited. This study evaluated the plasma pharmacokinetics (PK) and PTA of temocillin in non-critically ill cUTI patients with varying degrees of renal insufficiency (RI). Methods In this single-centre clinical study, 22 cUTI patients received a fixed 4 g/day (2 g q12h, intravenously) temocillin dose, irrespective of renal function (no RI: n  = 5, mild RI: n  = 8, moderate RI: n  = 9). Plasma samples were collected post-dosing for LC-MS analysis of total and unbound temocillin levels. Monte Carlo simulations were performed based on the established PK/PD target of ≥35% f T > MIC (minimal inhibitory concentration). Results Among patients, the highest plasma drug exposure and PK/PD target attainment were observed in those with moderate RI (median AUC0–12h = 1143 h.mg/L and % f T > MIC = 68%), followed by mild RI patients (median AUC0–12h = 918 h.mg/L and % f T > MIC = 34%), and the lowest in those with healthy kidney function (median AUC0–12h = 692 h.mg/L and % f T > MIC = 26%). Simulations indicated that the 4 g/day temocillin dose achieves 90% PTA only for glomerular filtration rate < 60 mL/min and MIC ≤ 8 mg/L. Conclusion The standard temocillin dose may need to be increased from 4 to 6 g/day to treat non-critically ill cUTI patients, in line with recent EUCAST recommendations. For patients with moderate RI, who experience higher exposure due to reduced renal drug clearance, 4 g/day temocillin remains appropriate. [ABSTRACT FROM AUTHOR]

In recent years, potential therapeutic applications of several different cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC), its isomer Δ8-THC and Δ9-tetrahydrocannabivarin (Δ9-THCV), have been investigated. Nevertheless, to establish dose–effect relationship and to gain knowledge of their pharmacokinetics and metabolism, sensitive and specific analytical assays are needed to measure these compounds in patients. For this reason, we developed and validated an online extraction high-performance liquid/liquid chromatography–tandem mass spectrometry (LC/LC–MS-MS) method for the simultaneous quantification of 13 cannabinoids and metabolites including the Δ8 and Δ9 isomers of THC, THCV and those of their major metabolites in human plasma. Plasma was fortified with cannabinoids at varying concentrations within the working range of the respective compound and 200 µL was extracted using a simple one-step protein precipitation procedure. The extracts were analyzed using online trapping LC/LC–atmospheric pressure chemical ionization–MS-MS running in the positive multiple reaction monitoring mode. The lower limit of quantification ranged from 0.5 to 2.5 ng/mL, and the upper limit of quantification was 400 ng/mL for all analytes. Inter-day analytical accuracy and imprecision ranged from 82.9% to 109% and 4.3% to 20.3% (coefficient of variance), respectively. Of 534 plasma samples following controlled oral administration of Δ8-THCV, 236 were positive for Δ8-THCV (median; interquartile ranges: 3.5 ng/mL; 1.8–11.9 ng/mL), 383 for the major metabolite (−)-11-nor-9-carboxy-Δ8-tetrahydrocannabivarin (Δ8-THCV-COOH) (95.4 ng/mL; 20.7–328 ng/mL), 260 for (−)-11-nor-9-carboxy-Δ9-tetrahydrocannabivarin (Δ9-THCV-COOH) (5.8 ng/mL; 2.5–16.1 ng/mL), 157 for (−)-11-hydroxy-Δ8-tetrahydrocannabivarin (11-OH-Δ8-THCV) (1.7 ng/mL; 1.0–3.7 ng/mL), 49 for Δ8-THC-COOH (1.7 ng/mL; 1.4–2.3 ng/mL) and 42 for Δ9-THCV (1.3 ng/mL; 0.8–1.6 ng/mL). We developed and validated the first LC/LC–MS-MS assay for the specific quantification of Δ8-THC, Δ9-THC and THCV isomers and their respective metabolites in human plasma. Δ8-THCV-COOH, 11-hydroxy-Δ8-THCV and Δ9-THCV-COOH were the major Δ8-THCV metabolites in human plasma after oral administration of 98.6% pure Δ8-THCV. [ABSTRACT FROM AUTHOR]

An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the determination of monocrotaline and usaramine in rat plasma, to study the plasma drug concentration and pharmacokinetics, and to calculate the absolute bioavailability. The plasma was treated with acetonitrile and methanol (9:1, v/v) protein precipitation method. The chromatographic column was UPLC HSS T3 (50 mm × 2.1 mm, 1.7 μm), the mobile phase was methanol-water (containing 0.1% formic acid with 10 mM ammonium acetate in water), and the elution time was 4 min at a flow rate of 0.4 mL min−1. Electrospray ionization (ESI) positive ion mode was used for detection and multiple reaction monitoring (MRM) mode was used for quantitative analysis. Monocrotaline and usaramine were administered sublingual intravenously (iv) 1 mg kg−1 and orally (po) 5 mg kg−1, respectively, with 6 rats in each group, for a total of 24 rats. Then the pharmacokinetic differences in rats were evaluated. For the UPLC-MS/MS method, the calibration curve showed good linearity in the range of 2–2,000 ng mL−1, where r was greater than 0.99. The precision, accuracy, recovery, matrix effect and stability results were all consistent with the requirements of biological sample detection methods. to provide scientific experimental basis for the basic research The bioavailability of monocrotaline and usaramine in rat plasma was calculated, which was 43.5 and 19.5%, respectively. [ABSTRACT FROM AUTHOR]

Introduction: Polymyxin B is widely used to treat infections caused by multidrug-resistant Gram-negative bacteria. However, the pharmacokinetic study data of PB in the elderly are scarce. Herein, a simple method to measure the concentration of PB in human plasma was developed and validated by high performance liquid chromatography--tandem mass spectrometry, and it was applied to a PK study in the elderly. Methods: PB was extracted from human plasma by a rapid protein-precipitation method using 0.1% formic acid in methanol and then separated on an ultimate AQ-C18 column using linear gradient elution with a 0.5-mL/min flow rate. Subsequently, PB was detected using a mass spectrometer operated in positive-ion and multiple-reaction-monitoring modes. Results: The lower limits of quantification of the method for Polymyxin B1 and Polymyxin B2 were 1.00 and 0.10 μg/mL, respectively. The linear ranges for PB1 and PB2 were 1.00-20.02 and 0.10-2.04 μg/mL, respectively. Patients receiving a 75-mg maintenance dose every 12h had AUCss, 24 h, and Css, av values of 117.70 ± 37.03 μg h/mL and 4.14 ± 1.74 μg/mL, respectively. For patients receiving a 100 mg maintenance dose, these values were 152.73 ± 70.09 μg h/mL and 5.43 ± 2.85 μg/mL, respectively. Conclusion: The validated HPLC--MS/MS method was successfully applied to a study on the pharmacokinetics of PB in elderly patients infected with multidrug-resistant Gram-negative bacteria. Both two dose strategies in this study would have a excessive PB exposure in the elderly patients then the therapeutic window recommended by guidelines. [ABSTRACT FROM AUTHOR]

Ginsenoside Compound K (GCK) is the main metabolite of natural protopanaxadiol ginsenosides with diverse pharmacological effects. Gut microbiota contributes to the biotransformation of GCK, while the effect of gut microbiota on the pharmacokinetics of GCK in vivo remains unclear. To illustrate the role of gut microbiota in GCK metabolism in vivo, a systematic investigation of the pharmacokinetics of GCK in specific pathogen free (SPF) and pseudo-germ-free (pseudo-GF) rats were conducted. Pseudo-GF rats were treated with non-absorbable antibiotics. Liquid chromatography tandem mass spectrometry (LC–MS/MS) was validated for the quantification of GCK in rat plasma. Compared with SPF rats, the plasma concentration of GCK significantly increased after the gut microbiota depleted. The results showed that GCK absorption slowed down, Tmax delayed by 3.5 h, AUC0-11 increased by 1.3 times, CLz/F decreased by 0.6 times in pseudo-GF rats, and Cmax was 1.6 times higher than that of normal rats. The data indicated that gut microbiota played an important role in the pharmacokinetics of GCK in vivo. [ABSTRACT FROM AUTHOR]

Native liquid chromatography mass spectrometry (LC-MS) is a commonly used approach for intact analysis of inter-chain cysteine conjugated antibody-drug conjugates (ADCs). Coupling native LC-MS with affinity capture provides a platform for intact ADC analysis from in vivo samples and characterisation of individual drug load species, specifically the impact of drug linker deconjugation, hydrolysis, and differential clearance in a biological system. This manuscript describes data generated from native LC-MS analysis of ADCs from human plasma, both in vitro incubations and clinical samples. It also details the pharmacokinetic (PK) model built to specifically characterise the disposition of individual drug load species from MMAE and MMAF interchain cysteine conjugated ADCs. In vitro deconjugation and hydrolysis rates were similar across both ADCs. Differential clearance of higher loaded species in vivo was pronounced for the MMAE conjugated ADC, while systemic elimination after accounting for deconjugation was similar across drug loads for the MMAF conjugated ADC. This is the first report of affinity capture native LC-MS analysis, and subsequent modelling of deconjugation, hydrolysis and clearance rates of individual drug load species using clinical data from cysteine conjugated ADCs. [ABSTRACT FROM AUTHOR]

Objectives: To describe the pharmacokinetic (PK) characteristics of nirmatrelvir/ritonavir in renal transplant recipients and explore the potential factors that related to the PK variance of nirmatrelvir/ritonavir and its interaction with calcineurin inhibitor (CNI). Methods: Renal transplant recipients treated with CNI and nirmatrelvir/ritonavir were prospectively enrolled. Steady-state plasma concentrations of nirmatrelvir/ritonavir were determined by high-performance liquid chromatography-tandem mass spectrometry, and the PK parameters were calculated using non-compartmental analysis. Spearman correlation analysis was used for exploring influencing factors. Results: A total of eight recipients were enrolled; for nirmatrelvir and ritonavir, AUC/dose was 0.24179 ± 0.14495 and 0.06196 ± 0.03767 μg·h·mL-1·mg-1. Red blood cell (RBC), hematocrit (Ht), hemoglobins (Hb), and creatinine clearance (Ccr) were negatively correlated with AUC/dose of nirmatrelvir, while Ccr, CYP3A5 genotype, and CYP3A4 genotype were related to the AUC/dose of ritonavir. Ccr was negatively correlated with the C0/dose of tacrolimus (TAC) after termination of nirmatrelvir/ritonavir (rs = -0.943, p = 0.008). Conclusions: The PK characteristics of nirmatrelvir/ritonavir vary greatly among renal transplant recipients. Factors including Ccr and CYP3A5 genotype were related to the in vivo exposure of nirmatrelvir/ritonavir. During the whole process before and after nirmatrelvir/ritonavir therapy, it is recommended to adjust the CNI basing on renal function to avoid CNI toxicity exposure. [ABSTRACT FROM AUTHOR]

Aims: Therapeutic drug monitoring (TDM) has led to significant improvements in individualized medical care, although its implementation in oncology has been limited to date. Tyrosine kinase inhibitors (TKIs) are a group of therapies for which TDM has been suggested. Osimertinib is one such therapy used in the treatment of epidermal growth factor receptor (EGFR) mutation‐driven lung cancer. Herein, we describe a prospective pilot study involving 21 patients on osimertinib primarily as a preliminary evaluation of drug levels in a real‐world setting. Methods: Concentrations of the drug and its primary metabolites were measured with a validated liquid chromatography–mass spectrometry (LC–MS) assay across serial timepoints. As part of this study, inter‐individual variability by dose and ethnicity as well as intra‐individual variability across timepoints are explored. Furthermore, we attempted to validate dried blood spot (DBS)‐based quantitation as an accurate alternative to plasma quantitation. Results: Successful quantitation of osimertinib and primary metabolites was achieved for our subjects. Compound plasma levels were highly correlated to DBS levels. There was no significant difference in concentrations with ethnicity or dosing or intra‐individual variability across timepoints. Conclusions: As such, we demonstrate that TDM for osimertinib is practical for future trials. We also validated the use of DBS as an alternative to conventional quantitation for exploration of TDM for osimertinib in larger trials and for other targeted therapies. [ABSTRACT FROM AUTHOR]

In this study, plasma belimumab concentrations were measured over the course of treatment in systemic lupus erythematosus (SLE) patients on belimumab therapy, and intra‐ and interindividual variations in plasma belimumab concentration were evaluated. A single‐center prospective study was conducted at Oita University Hospital to evaluate trough plasma concentrations over the course of treatment in 13 SLE patients treated with intravenous belimumab. Plasma belimumab concentrations were measured by a validated ultra‐high performance liquid chromatography with tandem mass spectrometry method. The median age of the patients was 40 (interquartile range: 35–51) years and the median weight was 51.8 (47.0–58.1) kg. A mean of 9.4 (range: 1–13) blood samples was collected per patient at routine visits. The mean (± SD) plasma belimumab concentration was 33.4 ± 11.9 μg/mL in the patient with the lowest concentration and 170.0 ± 16.6 μg/mL in the patient with the highest concentration, indicating a 5‐fold difference between patients. On the other hand, the within‐patient coefficient of variation ranged from 7.1% to 35.7%, showing no large variations. No significant correlation was observed between plasma belimumab concentration and belimumab dose (mg/kg) (Spearman's rank correlation coefficient = 0.22, p =.54). Examinations of trough plasma belimumab concentrations over the course of treatment in patients with SLE showed small intraindividual variation but large interindividual variation. Plasma belimumab trough concentration varied widely among patients administered the approved dose. [ABSTRACT FROM AUTHOR]

A sensitive UPLC-HRMS method was developed and validated for simultaneous quantification of four active flavonoids from Chimonanthus nitens Leaf Granules (CNLG) in biological matrix. The method was utilized in pharmacokinetic study of the four flavonoids in rats as well as other evaluation assays in vitro. It was revealed that rutin, nicotiflorin, and astragalin had poor oral bioavailability in rats possibly due to low intestinal permeability and metabolism in intestinal flora. Kaempferol underwent rapid glucuronidation and sulphation in rat plasma with medium permeability coefficient. The results provided valuable data for future research and development of CNLG flavonoids. [ABSTRACT FROM AUTHOR]

Myristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20 mg once daily (OD) to 210 mg OD without DLT, but gastrointestinal DLTS were seen in the 280 mg cohort. MTD and recommended phase 2 dose were 210 mg OD. Common adverse events were predominantly Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2 h with terminal half-lives averaging 10 h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210 mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted. [ABSTRACT FROM AUTHOR]

Multimodal analgesia is defined as using several drugs or techniques simultaneously to target different pain pathways or receptors to avoid pain propagation. This study evaluated the pharmacokinetic profile and comparative bioavailability of etoricoxib 90 mg and tramadol 50 mg dosing alone (reference drugs) or in a novel fixed‐dose combination (test drug) under fasting conditions in Mexican healthy volunteers. This was a randomized, open‐label, 3‐way, crossover, single‐dose, prospective, and longitudinal study with a 14‐day washout period. Eligible subjects were healthy Mexican adult volunteers. The drugs were dosing orally, according to the randomization sequence, after 10 hours of fasting and 4 hours before breakfast with 250 mL of water at room temperature. Serial blood samples were collected before and after dosing, both drugs were quantified using high‐performance liquid chromatography coupled with tandem mass spectrometry. Forty‐two subjects were enrolled and 38 completed the study (28 men and 14 women, mean age 25.2 years, mean weight 66.6 kg). Test products were considered to have comparative bioavailability if confidence intervals of natural log‐transformed for (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration‐time curve form 0 up to last sampling time (AUC0‐t), and (area under the plasma drug concentration‐time curve from 0 up to infinity (AUC0‐∞) data were within the range of 80%‐125%. Non‐serious adverse events were observed. The results demonstrate that the pharmacokinetic profile and bioavailability of the etoricoxib/tramadol fixed‐dose combination are comparable to those of the reference products. [ABSTRACT FROM AUTHOR]

Pulmonary Mycobacterium avium-intracellulare complex (MAC) disease is a typical non-tuberculous mycobacterial infection. The incidence of pulmonary MAC is increasing worldwide. This study aimed to clarify the pharmacokinetic parameters of anti-pulmonary MAC disease drugs in silkworms. The pharmacokinetic parameters investigated included maximum concentration, area under the concentration–time curve, total clearance, and volume of distribution at steady-state. In addition, protein-binding rates, fat body transferability, and drug-drug interactions were examined. Antibiotic concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry method. Among the antibiotics investigated, amikacin was not eliminated from silkworms during the 48-h observation period. In contrast, dose-proportional pharmacokinetics were observed in silkworms for all antibiotics tested, except for amikacin. Protein-binding rates in hemolymph for clarithromycin, azithromycin, rifampicin, ethambutol, and amikacin were 39.6 ± 3.0%, 39.5 ± 4.3%, 76.3 ± 3.2%, 20.9 ± 4.2%, and 73.1 ± 4.7%, respectively (mean ± standard deviation). The distribution of antibiotics in the fat bodies of silkworms was related to drug lipophilicity. No drug-drug interactions were observed in the silkworms. The pharmacokinetics of these drugs in silkworms differed significantly from those in humans. Therefore, while it is challenging to predict the pharmacokinetics of these drugs in humans based on silkworm data, the silkworm infection model has facilitated a comprehensive assessment of the relationship between antibiotic exposure and efficacy. [ABSTRACT FROM AUTHOR]

Background: Q808 is a novel antiepileptic agent currently in development. In this study, we established and validated a LC-MS/MS method for the quantification of Q808 in Rhesus monkey plasma. Furthermore, we applied this method to investigate the pharmacokinetics of Q808 in Rhesus monkeys. Methods: Samples containing diazepam as an internal standard (IS) were subjected to liquid-liquid extraction (LLE) and separated using a Zorbax Extend C18 column. The detection of Q808 and IS was performed using multiple reaction monitoring mode (MRM), specifically monitoring precursor-to-product ion transitions at m/z 297.9 to 213.9 and m/z 285.2 to 193.1 for Q808 and IS, respectively. For the pharmacokinetic study of Q808, a total of 30 healthy Rhesus monkeys (half male and half female) were administered single oral doses, single IV doses, or multiple oral doses of Q808. Blood samples were collected at predetermined time points for subsequent pharmacokinetic analysis. Results: The developed LC-MS/MS method exhibited linearity within the concentration range of 1.5-750 ng/mL with intra-day precision ≤8.3% and inter-day precision ≤14.6%. Additionally, accuracy was found to be ≤3.4%. In the pharmacokinetic study involving single oral doses of Q808 in Rhesus monkeys, Q808 was absorbed with a median time to peak plasma concentration ranging from 4.50-6.00 h and was eliminated with a terminal elimination half-life (t1/2) between 9.34-11.31 h. No definitive conclusion regarding linear pharmacokinetic characteristics could be drawn. The absolute bioavailability was determined as 20.95%, indicating limited systemic exposure after oral administration. Multiple dosing did not result in significant accumulation based on an accumulation factor Rac value of 1.31. Conclusion: We have successfully developed and validated a rapid yet sensitive LC-MS/MS method for quantifying levels of Q808 in rhesus monkey plasma for the first time. The determination method and pharmacokinetic characteristics of Q808 in rhesus monkey support the next steps in drug development. [ABSTRACT FROM AUTHOR]

Patients with diabetes face a 2‐4‐fold greater cardiovascular risk compared to those without diabetes. Both metformin and acetylsalicylic acid (aspirin) treatment have demonstrated a significant reduction in this risk. This single‐center, open‐label, sequence randomized, 2 × 2 crossover, single‐dose clinical trial evaluated the pharmacokinetics profile and comparative bioavailability of a novel oral fixed‐dose combination (FDC) of metformin/acetylsalicylic acid (500/100 mg tablet) versus the reference mono‐drugs administered concomitantly, metformin 500 mg tablet and acetylsalicylic acid 100 mg tablet, in 22 healthy Mexican adult volunteers under fasting conditions. Blood samples were collected predose and at specified intervals across a 24‐hour period following administration and were analyzed for metformin and salicylic acid using high‐performance liquid chromatography coupled with tandem mass spectrometry. Test products were considered to have comparative bioavailability if confidence intervals of natural log‐transformed (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration‐time curve form 0 up to last sampling time (AUC0‐t), and (area under the plasma drug concentration‐time cruve from 0 up to infinity (AUC0∞) data were within the range of 80%‐125%. The results obtained from the present clinical study demonstrate the comparative bioavailability of the FDC when compared with the coadministration of reference mono‐drugs. There were no adverse events or adverse reactions reported throughout the study. [ABSTRACT FROM AUTHOR]

Purpose: The study aimed to determine the typical clearance and volume of distribution values of tamsulosin in patients with benign prostatic hyperplasia (BPH), and to identify factors with a measurable impact on the drug's elimination. Methods: This open-label, single-arm population pharmacokinetic study involved 65 adult men with BPH who had been on tamsulosin therapy for at least seven days. The steady-state serum concentrations of tamsulosin were measured using liquid chromatography-tandem quadrupole mass spectrometry. Population pharmacokinetic parameters, their variability, and influencing factors were estimated based on a two-compartment pharmacokinetic model using NONMEM software. Results: The estimated tamsulosin clearance in BPH patients was 0.719 L/h, and the steady-state volume of distribution was 32 L. Neither renal nor liver function parameters had a statistically significant effect on tamsulosin clearance. However, a positive correlation was observed between hemoglobin levels and tamsulosin clearance in the BPH patient cohort. Conclusion: Our investigation reveals significant associations between tamsulosin pharmacokinetics and specific characteristics of patients with lower urinary tract symptoms (LUTS) due to BPH. The study highlights that tamsulosin clearance is associated with hemoglobin levels in patients with LUTS/BPH. This study underscores the importance of considering patient-specific factors when managing BPH treatment with tamsulosin, emphasizing associations rather than causative relationships. [ABSTRACT FROM AUTHOR]

Invasive fungal infections (IFIs) are growing in importance in veterinary and human medicine. IFIs such as aspergillosis, blastomycosis, coccidioidomycosis and histoplasmosis remain challenging to treat in dogs. Isavuconazole is a novel antifungal medication that, when compared to currently used azoles, has an expanded spectrum of antifungal activity Rudramurthy (2011), Pfaller (2013), Spec (2018), has more predictable pharmacokinetics in humans Desai (2016), Cojutti (2021) and may cause fewer side effects such as liver and renal toxicity Maertens (2016), DiPippo (2018). The pharmacokinetic profile and safety of isavuconazole in dogs has not yet been characterized. The purpose of this study was to evaluate the pharmacokinetics of isavuconazole in healthy dogs that received a single dose of the prodrug isavuconazonium sulfate. Using full crossover design, six healthy beagle dogs received isavuconazonium sulfate at a mean (+/- SD) dose of 20.6 (+/- 2.8) mg/kg orally and 21.8 (+/- 4.2) mg/kg intravenously. Plasma was collected for batched pharmacokinetic analysis of prodrug and metabolite, isavuconazole, by ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). The median (Q1-Q3) maximum isavuconazole peak plasma concentration was estimated at 3,876.5 (2,811.0–4,800.0) ng/mL following oral administration, with a median (Q1-Q3) peak level at 1.3 (1.0–2.0) hours. Following intravenous administration, the median (Q1-Q3) isavuconazole peak plasma concentration was estimated at 3,221.5 (2,241.5–3,609.0) ng/mL, with a median (Q1-Q3) peak level at 0.4 (0.3–0.6) hours. The median (Q1-Q3) half-life of isavuconazole was 9.4 (7.0–12.2) hours and 14.0 (8.1–21.7) hours for oral and intravenous routes, respectively. One dog received inadvertent subcutaneous drug administration without any apparent adverse effects. Another dog experienced an anaphylactic reaction following accidental rapid drug infusion. No other drug-related adverse events were observed. At dosages used in this study, healthy dogs achieved isavuconazole plasma levels comparable to human therapeutic targets, and when properly administered the drug was well-tolerated. [ABSTRACT FROM AUTHOR]

Eltrombopag, a nonpeptide thrombopoietin receptor agonist, is primarily used for treating immune thrombocytopenic purpura. The aim of this study was to investigate the pharmacokinetic profile and food‐drug interaction of test and reference eltrombopag olamine tablets among healthy Chinese volunteers. An open, randomized, single‐dose, 2‐period crossover design was employed, involving fasting and fed conditions with a 10‐day washout period. Ninety‐six healthy volunteers received a single oral dose of 25 mg of the 2 eltrombopag formulations, with 48 participants in each group: fasting volunteers and those consuming a high‐fat, low‐calcium meal. Plasma eltrombopag concentrations were analyzed using liquid chromatography‐tandem mass spectrometry, and pharmacokinetic parameters were derived from the concentration‐time profiles. The geometric mean ratios, with 90% confidence intervals, for the maximum plasma concentration, area under the concentration‐time curve from time 0 to the last measurable concentration, and area under the concentration‐time curve from time 0 to infinity fell within the bioequivalence acceptance criteria (80%‐125%) under both fasting and fed conditions, indicating bioequivalence between the test and reference formulations. Administration of eltrombopag with a high‐fat, low‐calcium diet reduced the net systemic exposure by approximately 40%. Adverse events were recorded, and no serious adverse events were observed in either fasting or fed conditions. In conclusion, eltrombopag is well tolerated and exhibits a favorable safety profile in the Chinese population. The achievement of bioequivalence under fasting and fed conditions supports the demonstration of biosimilarity between the test and reference formulations. [ABSTRACT FROM AUTHOR]

Astaxanthin (ATX) is a carotenoid nutraceutical with poor bioavailability due to its high lipophilicity. We tested a new tailored nanodroplet capable of solubilizing ATX in an oil-in-water micro-environment (LDS-ATX) for its capacity to improve the ATX pharmacokinetic profile and therapeutic efficacy. We used liquid chromatography tandem mass spectrometry (LC-MS/MS) to profile the pharmacokinetics of ATX and LDS-ATX, superoxide mutase (SOD) activity to determine their antioxidant capacity, protein carbonylation and lipid peroxidation to compare their basal and lipopolysaccharide (LPS)-induced oxidative damage, and ELISA-based detection of IL-2 and IFN-γ to determine their anti-inflammatory capacity. ATX and LDS-ATX corrected only LPS-induced SOD inhibition and oxidative damage. SOD activity was restored only by LDS-ATX in the liver and brain and by both ATX and LDS-ATX in muscle. While in the liver and muscle, LDS-ATX attenuated oxidative damage to proteins and lipids better than ATX; only oxidative damage to lipids was preferably corrected by LDS-ATX in the brain. IL-2 and IFN-γ pro-inflammatory response was corrected by LDS-ATX and not ATX in the liver and brain, but in muscle, the IL-2 response was not corrected and the IFN-γ response was mitigated by both. These results strongly suggest an organ-dependent improvement of ATX bioavailability and efficacy by the LDS-ATX nanoformulation. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions Yokukansan is one of the most frequently used herbal medicines that can improve the behavioral and psychological symptoms of dementia. In this exploratory study, we investigated whether yokukansan affects the steady‐state blood concentrations of donepezil, risperidone, and the major metabolites of both drugs in a real‐world clinical setting.A non‐randomized, open‐label, single‐arm study examining drug–drug interactions was conducted. Fifteen dementia patients taking donepezil for at least 4 weeks and eight schizophrenia patients taking risperidone for at least 2 weeks were orally administered 2.5 g of yokukansan three times a day before or between meals, and blood samples were collected before and 8 weeks after starting co‐treatment with yokukansan. Plasma concentrations of donepezil, risperidone, and each metabolite were measured using high‐performance liquid chromatography–tandem mass spectrometry and compared before and after the 8‐week administration of yokukansan.The plasma concentrations of donepezil and its metabolites (6‐O‐desmethyl‐donepezil, 5‐O‐desmethyl‐donepezil, and donepezil‐N‐oxide), risperidone, and its metabolite paliperidone did not differ before and after the 8‐week treatment with yokukansan.The findings of this study show that the concomitant use of yokukansan may have little clinical impact on the steady‐state blood levels of donepezil and risperidone in patients with dementia or schizophrenia. [ABSTRACT FROM AUTHOR]

In this study, a rapid and sensitive ultra‐high performance liquid chromatography‐tandem mass spectrometry method was established for the simultaneous determination of four Vitexin‐4"‐O‐glucoside (VOG), Vitexin‐2"‐O‐rhamnoside (VOR), vitexin (VIT), and hyperoside (HP) in plasma, which are representative flavonoids constituents of hawthorn leaves. The four components were separated by CORTECS UPLC C18 column (100 × 3.0 mm, 1.6 µm), using acetonitrile‐water containing 0.02% formic acid and 2 mmol/L ammonium formate as the mobile phase, the gradient elution flow rate was 0.30 mL/min. The analyte was quantified using an electrospray ionization triple quadrupole mass spectrometer. The analytes and baicalin internal standard were performed at m/z 593.2/413.2 for VOG, m/z 577.2/413.1 for VOR, m/z 431.1/310.9 for VIT, m/z 463.2/300 for HP and m/z 445.1/269 for internal standard. Among the four flavonoids, the correlation coefficient of the standard curve of each component is between 0.9939 and 0.9987. After oral administration of hawthorn leaf extract, VOG and VOR showed similar pharmacokinetic characteristics; VIT was eliminated in the body more slowly than the other three flavonoids and distributed more in the tissues; HP can be quickly absorbed in the blood. The developed analytical method has high sensitivity, precision, and accuracy with no interference from plasma components and has been successfully used in pharmacokinetic studies. [ABSTRACT FROM AUTHOR]

A high‐performance liquid chromatography‐tandem mass spectrometry method has been developed for the determination of irinotecan, 7‐ethyl‐10‐hydroxycamptothecin (SN38), and SN38 glucuronide (SN38G) in rat plasma in the present study. The analytes were separated on a C18 column and a triple‐quadrupole mass spectrometry equipped with an electrospray ionization source was applied for detection. Irinotecan, SN38 and SN38G could be well retained in the C18 column after optimization of mobile phase. A simple protein precipitation was used to pretreat the plasma. The extraction recovery was above 90% and the matrix effect could be negligible. The method was linear over the concentration ranges of 3.46–3458.8 ng/mL for irinotecan, 2.53–2530.0 ng/mL for SN38 and 2.5–2500.0 ng/mL for SN38G. The precision and accuracy was within the acceptable limits. The simple and convenient method was validated and successfully applied to support the pharmacokinetic study and elucidate the mechanism of irinotecan‐induced diarrhea after irinotecan was intravenously injected to the Sprague‐Dawley rats. [ABSTRACT FROM AUTHOR]

Background: Levodopa is the gold standard of treatment in Parkinson's disease (PD). Its clinical effect changes as the disease progresses. Wearing off is a frequent first manifestation of motor fluctuations. Some patients with advanced PD report faster wearing off after physical exercise. Objective: The aim was to assess if pharmacokinetics of levodopa is influenced by physical exercise in patients with different disease advancement. Methods: 22 patients with PD (12 untreated with levodopa and 10 with motor fluctuations) and 7 healthy controls (HC) were included. Plasma samples were collected at 9 fixed timepoints following administration of levodopa/benserazide 200/50 mg for two days: rest day and standardized physical exercise day. Clinical assessment with Unified Parkinson Disease Rating Scale part III (UPDRS III) was performed in fixed timepoints. Liquid chromatography-tandem mass spectrometry was used to measure levodopa concentrations. Results: No differences between the HC, levodopa naïve and advanced PD groups were observed regarding selected pharmacokinetic parameters. In advanced PD and HC no differences in pharmacokinetic parameters of levodopa with and without effort were observed. In levodopa naïve PD group higher mean residence time after rest than after exercise (168.9±48.3 min vs. 145.5±50.8 min; p = 0.026) was observed. In advanced PD group higher UPDRS III score (14.45±5.5 versus 20.9±6.1 points, p = 0.04) was observed after exercise. Conclusions: The deterioration of motor status of advanced PD patients after physical effort is not reflected by changes in pharmacokinetics but rather mediated by central mechanisms. Plain Language Summary: Background: Levodopa is an important treatment for Parkinson's disease (PD). As the disease gets worse, levodopa's effects change. A common problem is "wearing off," where the medicine stops working sooner than expected. Some advanced PD patients say this happens faster after they exercise. Study goals: The study aimed to find out if exercise changes how the body processes levodopa in patients at different stages of PD. Methods: Participants: 22 PD patients (12 not yet on levodopa and 10 advanced patients- treated with levodopa with "wearing off") and 7 healthy people. Procedure: Participants took levodopa/benserazide (200/50 mg) on two days: a rest day and an exercise day. Each day blood samples were collected at 9 set times to measure levodopa levels. PD symptoms were assessed using a scale called UPDRS III at specific times. Testing: Levodopa levels in blood were measured using a technique called liquid chromatography-tandem mass spectrometry. Results: No differences: There were no differences in how the body processed levodopa among healthy people, untreated PD patients, and advanced PD patients. Exercise impact: For both healthy people and advanced PD patients, exercise did not change how the body processed levodopa. Untreated patients: In PD patients not yet on levodopa, the medicine stayed in the body longer after rest compared to after exercise. Advanced PD patients: These patients had worse PD symptoms after exercise, but this was not due to changes in how levodopa was processed. Conclusion: The worsening of symptoms in advanced PD patients after exercise is not because of changes in levodopa levels. It likely involves other factors in the brain. [ABSTRACT FROM AUTHOR]

Background and Objectives: Clozapine is the medication of choice for treatment-resistant schizophrenia. However, it has a complex metabolism and unexplained interindividual variability. The current work aims to develop a pharmacokinetic model of clozapine and norclozapine in non-smokers and assess the impact of demographic and genetic predictors. Methods: Healthy volunteers were recruited in a population pharmacokinetic study. Blood samples were collected at 30 min and 1, 2, 3, 5 and 8 h following a single flat dose of clozapine (12.5 mg). The clozapine and norclozapine concentrations were measured via high-performance liquid chromatography–ultraviolet method. A semi-physiological pharmacokinetic model of clozapine and norclozapine was developed using nonlinear mixed-effects modeling. Clinical and genetic predictors were evaluated, including CYP1A2 (rs762551) and ABCB1 (rs2032582), using restriction fragment length polymorphism. Results: A total of 270 samples were collected from 33 participants. The data were best described using a two-compartment model for clozapine and a two-compartment model for norclozapine with first-order absorption and elimination and pre-systemic metabolism. The estimated (relative standard error) clearance of clozapine and norclozapine were 27 L h-1 (31.5 %) and 19.6 L h-1 (30%), respectively. Clozapine clearance was lower in sub-Saharan Africans (n = 4) and higher in Caucasians (n = 9) than Asians (n = 20). Participants with CYP1A2 (rs762551) (n = 18) and ABCB1 (rs2032582) (n = 12) mutant alleles had lower clozapine clearance in the univariate analysis. Conclusions: This is the first study to develop a semi-physiological pharmacokinetic model of clozapine and norclozapine accounting for the pre-systemic metabolism. Asians required lower doses of clozapine as compared with Caucasians, while clozapine pharmacokinetics in sub-Saharan Africans should be further investigated in larger trials. [ABSTRACT FROM AUTHOR]

Futibatinib is an excellent fibroblast growth factor receptor 1–4 (FGFR 1–4) inhibitor that exhibits selective anti-tumor activeness against FGFR-deregulated tumors. A new high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) technique for the quantitative analysis of futibatinib in beagle dog plasma was developed, and the effect of Yinchenhao decoction (YCHD) on the pharmacokinetics of futibatinib was evaluated. After processing plasma samples with ethyl acetate extraction in the alkaline condition of sodium carbonate, a C18 column (4.6 mm × 150, 5 μm) was used to accomplish the separation of futibatinib and ripretinib (internal standard, ISTD), with the mobile phase consisting of methanol and 0.1% formic acid in water (60:40). The scanning method adopted a multiple reaction monitoring (MRM) mode with positive ion detection through the triple quadrupole mass spectrometer. The ion transitions for futibatinib and IS were m/z 419.20 → 296.15 and m/z 510.36 → 417.00, respectively. Futibatinib displayed excellent linearity in the range of 1–200 ng/mL. Neither inter-day nor intra-day precision exceeded 6.3%. The %RE values for accuracy ranged from −3.1% to 0.9%. The recovery, stability, and matrix effect of futibatinib also complied with the guidelines for the validation of quantitative analysis methods for biological samples in the 2020 edition of the Chinese Pharmacopoeia. In combination with YCHD, the Cmax of futibatinib increased by 40.84% compared to futibatinib dosage alone., and the AUC(0–t) and AUC(0–∞) of futibatinib increased by 78.06% and 82.71%, respectively. The Vd and CL of futibatinib were reduced by 20.05% and 40.85%, respectively. T1/2 was extended from 3.88 h to 5.26 h. The results indicated that YCHD could affect the pharmacokinetics of futibatinib and increase the plasma exposure of futibatinib. If YCHD is administered along with futibatinib, this study gives a first impression how pharmacokinetics and toxicokinetics would change. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the plasma concentrations and determine the pharmacokinetic parameters of atorvastatin and its primary active metabolites (para- and orthohydroxyatorvastatin) after administration of a single oral dose in cockatiels (Nymphicus hollandicus). ANIMALS: 14 adult cockatiels (7 male, 7 female) around 2 years of age. METHODS: A compounded oral suspension of atorvastatin 10 mg/mL made with an oral suspending agent and an oral sweetener was administered via oral gavage at 20 mg/kg to each bird. Blood samples were collected at 7 different time points from 0.5 to 24 hours postadministration in a balanced incomplete block design with 3 blood samples per bird and 6 replicates per time point. Plasma concentrations of atorvastatin, parahydroxyatorvastatin, and orthohydroxyatorvastatin were determined by liquid chromatography-tandem mass spectrometry. Pharmacokinetic analysis was performed using noncompartmental analysis. RESULTS: The estimated time to maximum concentration (tmax) for atorvastatin, parahydroxyatorvastatin, and orthohydroxyatorvastatin was 3 hours for each. The estimated maximum plasma concentration (Cmax) for atorvastatin, parahydroxyatorvastatin, and orthohydroxyatorvastatin was 152.6, 172.4, and 68.8 ng/mL, respectively. The terminal halflives were 4, 6.8, and 4.6 hours, respectively. CLINICAL RELEVANCE: These results support the therapeutic use of atorvastatin at the dose evaluated in this species based on human pharmacokinetic data. A starting dose of 20 mg/kg PO every 12 to 24 hours could be used to treat lipid disorders in cockatiels pending more data on multidose use and hypolipidemic efficacy. [ABSTRACT FROM AUTHOR]

Lameness is a significant welfare concern in goats. Amphotericin B is used via intraarticular (IA) administration in models to study experimentally induced lameness in large animals. The main objective of this study was to estimate plasma pharmacokinetic (PK) parameters for amphotericin B in goats after a single IA administration. Liposomal amphotericin B was administered to ten Kiko‐cross goats at a dose of 10 mg total (range: 0.34–0.51 mg/kg) via IA administration into the right hind lateral distal interphalangeal joint. Plasma samples were collected over 96 h. Amphotericin B concentrations were measured via liquid chromatography/mass spectrometry (LC–MS/MS). A non‐compartmental analysis was used to derive PK parameters. Following single IA administration, maximum plasma concentration was estimated at 54.6 ± 16.5 ng/mL, and time to maximum concentration ranged from 6 to 12 h. Elimination half‐life was estimated at 30.9 ± 16.5 h, and mean residence time was 45.1 ± 10.4 h. The volume of distribution after IA administration was 13.3 ± 9.4 L/kg. The area under the curve was 1481 ± 761 h*ng/mL. The achieved maximum concentration was less than the observed concentrations for other species and routes of administration. Further research is needed into the pharmacodynamics of IA liposomal amphotericin B in goats to determine specific research strategies. [ABSTRACT FROM AUTHOR]

Invasive fungal aspergillosis is a leading cause of morbidity and mortality in many species including avian species such as common ravens (Corvus corax). Methods were developed for mass spectral determination of voriconazole in raven plasma as a means of determining pharmacokinetics of this antifungal agent. Without further development, GC/MS/MS (gas chromatography-tandem quadrupole mass spectrometry) proved to be inferior to LC/MS/MS (liquid chromatography-tandem quadrupole mass spectrometry) for measurement of voriconazole levels in treated raven plasma owing to numerous heat-induced breakdown products despite protection of voriconazole functional groups with trimethylsilyl moieties. LC/MS/MS measurement revealed in multi-dosing experiments that the ravens were capable of rapid or ultrarapid metabolism of voriconazole. This accounted for the animals' inability to raise the drug into the therapeutic range regardless of dosing regimen unless cytochrome P450 (CYP) inhibitors were included. Strategic selection of CYP inhibitors showed that of four selected compounds including cimetidine, enrofloxacin and omeprazole, only ciprofloxacin (Cipro) was able to maintain voriconazole levels in the therapeutic range until the end of the dosing period. The optimal method of administration involved maintenance doses of voriconazole at 6 mg/kg and ciprofloxacin at 20 mg/kg. Higher doses of voriconazole such as 18 mg/kg were also tenable without apparent induction of toxicity. Although most species employ CYP2C19 to metabolize voriconazole, it was necessary to speculate that voriconazole might be subject to metabolism by CYP1A2 in the ravens to explain the utility of ciprofloxacin, a previously unknown enzymatic route. Finally, despite its widespread catalog of CYP inhibitions including CYP1A2 and CYP2C19, cimetidine may be inadequate at enhancing voriconazole levels owing to its known effects on raising gastric pH, a result that may limit voriconazole solubility. [ABSTRACT FROM AUTHOR]

Aim: A precise, linear and specific liquid chromatography-tandem mass spectrometry procedure was executed and subjected for validation for the quantification of plasma. Materials and Methods: The chromatography elution was carried out using a C18-Discovery column of 15 cm in length and 2.1 mm in internal diameter, packed with stationary phase particles of 5 µm size, at a flow rate of 0.80 mL/min. An isocratic elution process was conducted with a mobile phase solution consisting of methanol and 0.10% V/V HCOOH in a ratio of 90:10. The separation of Abametapir and Metformin was achieved by a liquid-liquid extraction process using ethyl acetate as the solvent. Results: A triple quadrupole mass spectrometer was used for the measurement of ions. Electrospray ionization is a technology that ionizes positively, and it was used in Multiple Reaction Monitoring (MRM) with parent/product ionic transitions m/z 185.1→106.06 for Abametapir and 130.1→60.20 for the Metformin internal standard. A calibration graph was constructed with values ranging from 2.05 to 82.00 ng/mL, resulting in the equation y=0.0149x+0.00221, with a r2 value above 0.99. The recovery values of Abametapir exceeded 94.27%, with its accuracy assessed in terms of relative error ranging from -4.04% to 6.52%. Conclusion: The accuracy, recovery and sensitivity values of Abametapir in the plasma sample, as shown by the established approach, highlight its significance in pharmacokinetic and bioequivalence research. [ABSTRACT FROM AUTHOR]

Background and Objective: Ginseng has been regarded as a precious medicinal herb with miraculous effects in Eastern culture. The primary chemical constituents of ginseng are saponins, and the physiological activities of ginsenosides determine their edible and medicinal value. The aim of this study is to comprehensively and systematically investigate the kinetic processes of 20(S)--protopanaxadiol (PPD) in rats and dogs, in order to promote the rational combination of ginseng as a drug and dietary ingredient. Methods: PPD was administered, and drug concentration in different biological samples were detected by liquid chromatography tandem mass spectrometry (LC/MS/MS) and radioactive tracer methods. Pharmacokinetic parameters such as absorption, bioavailability, tissue distribution, plasma protein binding rate, excretion rate, and cumulative excretion were calculated, along with inference of major metabolites. Results: This study systematically investigated the absorption, distribution, metabolism, excretion (ADME) of PPD in rats and dogs for the first time. The bioavailabilities of PPD were relatively low, with oral absorption nearly complete, and the majority underwent first-pass metabolism. PPD had a high plasma protein binding rate and was relatively evenly distributed in the body. Following oral administration, PPD underwent extensive metabolism, potentially involving one structural transformation and three hydroxylation reactions. The metabolites were primarily excreted through feces and urine, indicating the presence of enterohepatic circulation. The pharmacokinetic processes of PPD following intravenous administration aligned well with a three-compartment model. In contrast, after gastric administration, it fitted better with a two-compartment model, conforming to linear pharmacokinetics and proportional elimination. There were evident interspecies differences between rats and dogs regarding PPD, but individual variations of this drug were minimal within the same species. Conclusion: This study systematically studied the kinetic process of PPD in rats and also investigated the kinetic characteristics of PPD in dogs for the first time. These findings lay the foundation for further research on the dietary nutrition and pharmacological effects of PPD. [ABSTRACT FROM AUTHOR]

Objective: N-butylphthalide (NBP) is a monomeric compound extracted from natural plant celery seeds, whether intestinal microbiota alteration can modify its pharmacokinetics is still unclear. The purpose of this study is to investigate the effect of intestinal microbiota alteration on the pharmacokinetics of NBP and its related mechanisms. Methods: After treatment with antibiotics and probiotics, plasma NBP concentrations in SD rats were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The effect of intestinal microbiota changes on NBP pharmacokinetics was compared. Intestinal microbiota changes after NBP treatment were analyzed by 16S rRNA sequencing. Expressions of CYP3A1 mRNA and protein in the liver and small intestine tissues under different intestinal flora conditions were determined by qRT-PCR and Western Blot. KEGG analysis was used to analyze the effect of intestinal microbiota changes on metabolic pathways. Results: Compared to the control group, the values of Cmax, AUC0-8, AUC0-∞, t1/2 in the antibiotic group increased by 56.1% (P<0.001), 56.4% (P<0.001), 53.2% (P<0.001), and 24.4% (P<0.05), respectively. In contrast, the CL and Tmax values decreased by 57.1% (P<0.001) and 28.6% (P<0.05), respectively. Treatment with antibiotics could reduce the richness and diversity of the intestinal microbiota. CYP3A1 mRNA and protein expressions in the small intestine of the antibiotic group were 61.2% and 66.1% of those of the control group, respectively. CYP3A1 mRNA and protein expressions in the liver were 44.6% and 63.9% of those in the control group, respectively. There was no significant change in the probiotic group. KEGG analysis showed that multiple metabolic pathways were significantly down-regulated in the antibiotic group. Among them, the pathways of drug metabolism, bile acid biosynthesis and decomposition, and fatty acid synthesis and decomposition were related to NBP biological metabolism. Conclusion: Antibiotic treatment could affect the intestinal microbiota, decrease CYP3A1 mRNA and protein expressions and increase NBP exposure in vivo by inhibiting pathways related to NBP metabolism. [ABSTRACT FROM AUTHOR]

An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was utilized to develop a technique for the simultaneous quantification of icariin and its primary metabolites in mouse urine. The levels of icariin, icariside Ⅰ, icariside Ⅱ, baohuoside Ⅱ, wushanicaritin, icaritin, and desmethylicaritin in mouse urine were analyzed subsequent to the oral administration of an icariin suspension. This study aimed to preliminarily investigate the excretion profile of icariin in mice. Using an aqueous solution containing 0.1% formic acid (A) and an acetonitrile solution containing 0.1% formic acid (B) as the mobile phases, icariin and its major metabolites demonstrated satisfactory linearity over the concentration range of 0.25–800 ng·mL−1 . The precision and accuracy of intra-day and inter-day measurements were all found to be within 15%. Seventy-two hours after the intragastric administration of icariin suspension to a mouse, the cumulative urinary excretion of icariin, icariside Ⅰ, icariside Ⅱ, baohuoside Ⅱ, wushanicaritin, icaritin, and desmethylicaritin was quantified as 13.48, 18.70, 2,627.51, 2.04, 10.04, 3,420.44, and 735.13 ng, respectively. The UPLC-MS/MS method developed in this research is characterized by its simplicity, sensitivity, and speed, making it well-suited for the concurrent quantification of icariin and its associated metabolites in urine. Additionally, it is appropriate for analyzing urine samples that may contain multiple drugs in future investigations. [ABSTRACT FROM AUTHOR]

Background and purposes: It is unclear whether the parent Saxagliptin (SAX) in vivo is the same as that in vitro, which is twice that of 5-hydroxy Saxagliptin (5-OH SAX). This study is to construct a Pharmacokinetic-Pharmacodynamic (PK-PD) link model to evaluate the genuine relationship between the concentration of parent SAX in vivo and the effect. Methods: First, we established a reliable Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS) method and DPP-4 inhibition ratio determination method. Then, the T2DM rats were randomly divided into four groups, intravenous injection of 5-OH SAX (0.5 mg/kg) and saline group, intragastric administration of SAX (10 mg/kg) and Sodium carboxymethyl cellulose (CMC-Na) group. Plasma samples were collected at different time points for subsequent testing. Finally, we used the measured concentrations and inhibition ratios to construct a PK-PD link model for 5-OH SAX and parent SAX. Results: A two-compartment with additive model showed the pharmacokinetic process of SAX and 5-OH SAX, the concentration-effect relationship was represented by a sigmoidal Emax model and sigmoidal Emax with E0 model for SAX and 5-OH SAX, respectively. Fitting parameters showed SAX was rapidly absorbed after administration (Tmax=0.11 h, t1/2, ka=0.07 h), widely distributed in the body (V ≈ 20 L/kg), plasma exposure reached 3282.06 ng*h/mL, and the elimination half-life was 6.13 h. The maximum plasma dipeptidyl peptidase IV (DPP-4) inhibition ratio of parent SAX was 71.47%. According to the final fitting parameter EC50, EC50, 5−OH SAX=0.46EC50, SAX(parent), it was believed that the inhibitory effect of 5-OH SAX was about half of the parent SAX, which is consistent with the literature. Conclusions: The PK-PD link model of the parent SAX established in this study can predict its pharmacokinetic process in T2DM rats and the strength of the inhibitory effect of DPP-4 based on non-clinical data. [ABSTRACT FROM AUTHOR]

Background: Tacrolimus (Tac) is commonly used for postoperative immunosuppressive therapy in transplant patients. However, problems, for example, low bioavailability and unstable plasma concentration, persist for a long time, Studies have reported that the deoxyschizandrin could effectively improve these problems, but the pharmacokinetic parameters (PKs) of Tac combined with deoxyschizandrin are still unknown. Method: In this study, an UHPLC-MS/MS method has been established for simultaneous quantitation of Tac and deoxyschizandrin. The PKs of Tac influenced by different doses of deoxyschizandrin after single and multiple administrations were analyzed, and the different impact of deoxyschizandrin and Wuzhi capsule on PKs of Tac were compared. Result: The modified UHPLC-MS/MS method could rapid quantification of Tac and deoxyschizandrin within 2 min using bifendatatum as the internal standard (IS). All items were successfully validated. The Cmax of deoxyschizandrin increased from 148.27 ± 23.20 to 229.13 ± 54.77 ng/mL in rats after multiple administrations for 12 days. After co-administration of 150 mg/mL deoxyschizandrin, Tac had an earlier Tmax and greater Cmax and AUC0-t, and the Cmax and AUC0-t of Tac increased from 14.26 ± 4.73 to 54.48 ± 14.37 ng/mL and from 95.10 ± 32.61 to 315.23 ± 92.22 h/ng/mL, respectively; this relationship was positively proportional to the dosage of deoxyschizandrin. In addition, compared with Wuzhi capsule, the same dose of deoxyschizandrin has a better effective on Tac along with more stable overall PKs. Conclusion: An UHPLC-MS/MS method was established and validated for simultaneous detection of deoxyschizandrin and Tac. Deoxyschizandrin could improve the in vivo exposure level and stability of Tac, besides, this effect is better than Wuzhi capsule in same dose. [ABSTRACT FROM AUTHOR]

Genetic variation among inhaled corticosteroid (ICS)-metabolizing enzymes may affect asthma control, but evidence is limited. This study tested the hypothesis that single-nucleotide polymorphisms (SNPs) in Cytochrome P450 3A5 (CYP3A5) would affect asthma outcomes. Patients aged 2–18 years with persistent asthma were recruited to use the electronic AsthmaTracker (e-AT), a self-monitoring tool that records weekly asthma control, medication use, and asthma outcomes. A subset of patients provided saliva samples for SNP analysis and participated in a pharmacokinetic study. Multivariable regression analysis adjusted for age, sex, race, and ethnicity was used to evaluate the impact of CYP3A5 SNPs on asthma outcomes, including asthma control (measured using the asthma symptom tracker, a modified version of the asthma control test or ACT), exacerbations, and hospital admissions. Plasma corticosteroid and cortisol concentrations post-ICS dosing were also assayed using liquid chromatography–tandem mass spectrometry. Of the 751 patients using the e-AT, 166 (22.1%) provided saliva samples and 16 completed the PK study. The e-AT cohort was 65.1% male, and 89.6% White, 6.0% Native Hawaiian, 1.2% Black, 1.2% Native American, 1.8% of unknown race, and 15.7% Hispanic/Latino; the median age was 8.35 (IQR: 5.51–11.3) years. CYP3A5*3/*3 frequency was 75.8% in White subjects, 50% in Native Hawaiians and 76.9% in Hispanic/Latino subjects. Compared with CYP3A5*3/*3, the CYP3A5*1/*x genotype was associated with reduced weekly asthma control (OR: 0.98; 95% CI: 0.97–0.98; p < 0.001), increased exacerbations (OR: 6.43; 95% CI: 4.56–9.07; p < 0.001), and increased asthma hospitalizations (OR: 1.66; 95% CI: 1.43–1.93; p < 0.001); analysis of 3/*3, *1/*1 and *1/*3 separately showed an allelic copy effect. Finally, PK analysis post-ICS dosing suggested muted changes in cortisol concentrations for patients with the CYP3A5*3/*3 genotype, as opposed to an effect on ICS PK. Detection of CYP3A5*3/3, CYPA35*1/*3, and CYP3A5*1/*1 could impact inhaled steroid treatment strategies for asthma in the future. [ABSTRACT FROM AUTHOR]

Epimedium-Rhizoma drynariae (EP-RD) was a well-known herb commonly used to treat bone diseases in traditional Chinese medicine. Nevertheless, there was incomplete pharmacokinetic behavior, metabolic conversion and chemical characterization of EP-RD in vivo. Therefore, this study aimed to establish metabolic profiles combined with multicomponent pharmacokinetics to reveal the in vivo behavior of EP-RD. Firstly, the diagnostic product ions (DPIs) and neutral losses (NLs) filtering strategy combined with UHPLC-Q-Orbitrap HRMS for the in vitro chemical composition of EP-RD and metabolic profiles of plasma, urine, and feces after oral administration of EP-RD to rats were proposed to comprehensively characterize the 47 chemical compounds and the 97 exogenous in vivo (35 prototypes and 62 metabolites), and possible biotransformation pathways of EP-RD were proposed, which included phase I reactions such as hydrolysis, hydrogenation, dehydrogenation, hydroxylation, dehydroxylation, isomerization, and demethylation and phase II reactions such as glucuronidation, acetylation, methylation, and sulfation. Moreover, a UHPLC-MS/MS quantitative approach was established for the pharmacokinetic analysis of seven active components: magnoflorine, epimedin A, epimedin B, epimedin C, icariin, baohuoside II, and icariin II. Results indicated that the established method was reliably used for the quantitative study of plasma active ingredients after oral administration of EP-RD in rats. Compared to oral EP alone, the increase in area under curves and maximum plasma drug concentration (P < 0.05). This study increased the understanding of the material basis and biotransformation profiles of EP-RD in vivo, which was of great significance in exploring the pharmacological effects of EP-RD. [ABSTRACT FROM AUTHOR]

BLU-945, a new-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is a potential drug candidate for the treatment of non-small-cell lung cancer (NSCLC) in patients with mutations that are resistant to previous generations of EGFR TKI. This compound has been investigated in preclinical and phase 1 dose-escalation studies that require a bioanalytical method for drug quantitation. In this study, an LC–MS/MS method was developed and validated for the quantitation of BLU-945 in rodent plasma and was applied to pharmacokinetic studies. The compound was extracted from plasma samples using a simple protein precipitation method. The method was validated in the linearity range of 1–1000 ng/mL with acceptable accuracy and precision, no matrix effects, and complete extraction recovery. BLU-945 was stable in the plasma quality control samples under various handling and storage conditions. The compound was stable after 4-h incubation in human, mouse, and rat plasma but was extensively metabolized in the microsomal fractions of these species. Furthermore, the validated analytical method was applied to a pharmacokinetic study in rats, revealing that BLU-945 had a high oral bioavailability range (55.91–105.6%) with a nonlinear pharmacokinetic profile up to an oral dose of 20 mg/kg. The validated bioanalytical method and findings of our study represent valuable assets for future investigations and clinical studies of BLU-945. [ABSTRACT FROM AUTHOR]

Background: With only one 15 mg primaquine tablet registered by a stringent regulatory authority and marketed, more quality-assured primaquine is needed to meet the demands of malaria elimination. Methods: A classic, two sequence, crossover study, with a 10-day wash out period, of 15 mg of IPCA-produced test primaquine tablets and 15 mg of Sanofi reference primaquine tablets was conducted. Healthy volunteers, aged 18–45 years, without glucose-6-phosphate dehydrogenase deficiency, a baseline haemoglobin ≥ 11 g/dL, creatinine clearance ≥ 70 mL/min/1.73 ms, and body mass index of 18.5–30 kg/m2 were randomized to either test or reference primaquine, administered on an empty stomach with 240 mL of water. Plasma primaquine and carboxyprimaquine concentrations were measured at baseline, then 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.333, 2.667, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0 and 72.0 h by liquid chromatography coupled to tandem mass spectrometry. Primaquine pharmacokinetic profiles were evaluated by non-compartmental analysis and bioequivalence concluded if the 90% confidence intervals (CI) of geometric mean (GM) ratios of test vs. reference formulation for the peak concentrations (Cmax) and area under the drug concentration–time (AUC0–t) were within 80.00 to 125.00%. Results: 47 of 50 volunteers, median age 33 years, completed both dosing rounds and were included in the bioequivalence analysis. For primaquine, GM Cmax values for test and reference formulations were 62.12 vs. 59.63 ng/mL, resulting in a GM ratio (90% CI) of 104.17% (96.92–111.96%); the corresponding GM AUC0–t values were 596.56 vs. 564.09 ngxh/mL, for a GM ratio of 105.76% (99.76–112.08%). Intra-subject coefficient of variation was 20.99% for Cmax and 16.83% for AUC0–t. Median clearances and volumes of distribution were similar between the test and reference products: 24.6 vs. 25.2 L/h, 189.4 vs. 191.0 L, whilst the median half-lives were the same, 5.2 h. Conclusion: IPCA primaquine was bioequivalent to the Sanofi primaquine. This opens the door to prequalification, registration in malaria endemic countries, and programmatic use for malaria elimination. Trial registration The trial registration reference is ISRCTN 54640699 [ABSTRACT FROM AUTHOR]

Objective. Pharmacokinetic parametric images obtained through dynamic fluorescence molecular tomography (DFMT) has ability of capturing dynamic changes in fluorescence concentration, thereby providing three-dimensional metabolic information for applications in biological research and drug development. However, data processing of DFMT is time-consuming, involves a vast amount of data, and the problem itself is ill-posed, which significantly limits the application of pharmacokinetic parametric images reconstruction. In this study, group sparse-based Taylor expansion method is proposed to address these problems. Approach. Firstly, Taylor expansion framework is introduced to reduce time and computational cost. Secondly, group sparsity based on structural prior is introduced to improve reconstruction accuracy. Thirdly, alternating iterative solution based on accelerated gradient descent algorithm is introduced to solve the problem. Main results. Numerical simulation and in vivo experimental results demonstrate that, in comparison to existing methods, the proposed approach significantly enhances reconstruction speed without a degradation of quality, particularly when confronted with background fluorescence interference from other organs. Significance. Our research greatly reduces time and computational cost, providing strong support for real-time monitoring of liver metabolism. [ABSTRACT FROM AUTHOR]

Introduction: Pogostemon cablin (PC) is used in traditional Chinese medicine and food, as it exerts pharmacological effects, such as immune-modulatory, antibacterial, antioxidant, antitumor, and antiviral. Currently, the pharmacokinetics (PK) studies of PC mainly focus on individual components. However, research on these individual components cannot reflect the actual PK characteristics of PC after administration. Therefore, the simultaneous determination of multiple components in rat plasma using UPLC-MS/MS was used for the pharmacokinetic study after oral administration of PC extract in this study, providing reference value for the clinical application of PC. Methods: In the present study, a reliable and sensitive ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous determination of 15 prototype components (vanillic acid, vitexin, verbascoside, isoacteoside, hyperoside, cosmosiin, apigenin, β-rhamnocitrin, acacetin, ombuin, pogostone, pachypodol, vicenin-2, retusin, and diosmetin-7-O-β-D-glucopyranoside) in rat plasma after oral administration of the PC extract. Plasma samples were prepared via protein precipitation using acetonitrile, and icariin was used as the internal standard (IS). Results: The intra-day and inter-day accuracies ranged from -12.0 to 14.3%, and the precision of the analytes was less than 11.3%. The extraction recovery rate of the analytes ranged from 70.6-104.5%, and the matrix effects ranged from 67.4-104.8%. Stability studies proved that the analytes were stable under the tested conditions, with a relative standard deviation lower than 14.1.% Conclusion: The developed method can be applied to evaluate the PK of 15 prototype components in PC extracts of rats after oral administration using UPLC-MS/MS, providing valuable information for the development and clinical safe, effective, and rational use of PC. [ABSTRACT FROM AUTHOR]