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Di-isodecyl phthalate (DiDP) is a high-molecular-weight phthalate that is mainly used as a plasticizer for plastics. Therefore, exposure to DiDP in the environment has become common with the increasing use of plastics around the world. Environmental regulations and scientific risk management for DiDP, which can be associated with endocrine disruption and various metabolic diseases, are urgently needed. The purpose of this study was to provide useful reference material for future human DiDP risk assessments by conducting toxicokinetic studies on DiDP. Rats were given 100 mg/kg of DiDP orally or intravenously, and plasma, urine, feces, and various tissues were sampled at preset times. DiDP and its major metabolites mono-isodecyl-phthalate (MiDP), mono-hydroxy-isodecyl-phthalate (MHiDP), mono-carboxy-isononyl-phthalate (MCiNP), and mono-oxo-isodecyl-phthalate (MOiDP) were simultaneously quantified from collected biological samples through the application of a newly developed and verified ultrahigh-performance liquid chromatography-electrospray ionization-tandem mass spectrometer (UHPLC-ESI-MS/MS) method. Based on the quantitative results for each analyte, toxicokinetic analyses were performed. DiDP was rapidly and extensively metabolized to MiDP, MHiDP, MCiNP, and MOiDP. The major metabolite excreted in the urine was MCiNP, suggesting that it could be a useful biomarker. The conjugated forms of DiDP and its metabolites have been significantly quantified in the plasma, urine, and feces. DiDP and its major metabolites were also distributed in various tissues in significant quantities. The toxicokinetic properties of DiDP, which have not been clearly reported previously, were identified through this study. This report will serve as a useful reference for future DiDP environmental regulation and scientific human risk assessment studies.

In our previous study, a long-acting injectable (LAI) formulation of finasteride was prepared as a new dosage form of PROPECIA®, and in vivo pharmacokinetics (PKs)-pharmacodynamics (PDs) was evaluated in beagle dogs. The resulting PK-PD profiles of the formulation showed pharmacological effects and achievability for monthly delivery. In this study, a first-in-human (FIH) dose of the LAI formulation loaded with finasteride was predicted. The three approaches were used for estimating a FIH dose of the LAI formulation: (1) No observed adverse effect level (NOAEL)-based approach; (2) Pharmacokinetically-guided approach; (3) Pharmacokinetic/pharmacodynamic model-based approach. The advantage, assumptions, limitations, and estimated FIH dose from each approach was discussed and compared since there is no consensus on the best approach. For the prediction of clinical exposures and estimation of FIH doses, the clinical PK-PD parameters were allometrically scaled from the nonclinical data, extracted from reported clinical studies, or fixed from published literature. The starting dose range of the LAI formulation (as finasteride) was estimated to be 16.80-81.06 mg from the three approaches, and the PK/PD model-based approach suggests the most optimal starting dose (16.80 mg) of the LAI formulation. The approaches for estimating starting doses presented in the study could be used as a basis for an Investigational New Drug (IND) application of new dosage forms.

As a toxic substance, 4-n-nonylphenol (4-n-NP) or 4-nonylphenol (4-NP) is widely present in the environment. 4-n-NP is a single substance with a linear-alkyl side chain, but 4-NP usually refers to a random mixture containing various branched types. Unfortunately, human risk assessment and/or exposure level analysis for 4-n-NP (or 4-NP) were almost nonexistent, and related research was urgently needed. This study aimed to analyze the various exposures of 4-n-NP (or 4-NP) through development of a physiologically based-pharmacokinetic (PBPK) model considering gender difference in pharmacokinetics of 4-n-NP and its application to human risk assessment studies. A PBPK model was newly developed considering gender differences in 4-n-NP pharmacokinetics and applied to a human risk assessment for each gender. Exposure analysis was performed using a PBPK model that considered gender differences in 4-n-NP (or 4-NP) exposure and high variabilities in several countries. Furthermore, an extended application was attempted as a human risk assessment for random mixture 4-NP, which is difficult to accurately evaluate in reality. External-exposure and margin-of-safety estimated with the same internal exposure amount differed between genders, meaning the need for a differentiated risk assessment considering gender. Exposure analysis based on biomonitoring data confirmed large variability in exposure to 4-n-NP (or 4-NP) by country, group, and period. External-exposures estimated using PBPK model varied widely, ranging from 0.039 to 63.875 mg/kg/day (for 4-n-NP or 4-NP). By country, 4-n-NP (or 4-NP) exposure was higher in females than in males and the margin-of-safety tended to be low. Overall, exposure to 4-n-NP (or 4-NP) in populations was largely not safe, suggesting need for ongoing management and monitoring. Considering low in vivo accumulation confirmed by PBPK model, risk reduction of 4-n-NP is possible by reducing its use.

Gumiganghwal-tang is a traditional herbal medicine widely used for its anti-inflammatory, analgesic, and antipyretic effects. However, the safety and efficacy of its active ingredients based on an in vivo pharmacokinetic (PK) study have yet been investigated. We have established a sensitive and accurate UPLC-ESI-MS/MS method and conducted a PK study on 14 constituents of Gumiganghwal-tang through human plasma analysis. Analytical conditions were optimized according to the physicochemical properties of the 14 compounds to facilitate efficient separation and eliminate overlap or interference between peaks. KINETEX-C18 and Inertsil-C8 columns were used as UPLC stationary phases, and acetonitrile and aqueous formic acid were used as mobile phases. All the analytes were quantified with a triple quadrupole mass spectrometer using electrospray ionization in multiple reaction monitoring mode. The chromatograms of 14 bioactive compounds showed excellent elution and sensitivity, and each peak was selectively separated and quantified without interference with each other or impurities. The established analytical method was based on international guidelines and was successfully used to perform PK studies of 14 herbal ingredients in humans after oral administration with Gumiganghwal-tang tablets. The oral absorption of most active components of Gumiganghwal-tang was relatively rapid and remained considerably long in the body to be quantified in plasma up to 48 h after administration., Graphical abstract Image 1, Highlights • Establishment and validation of simultaneous analysis of Gumiganghwal-tang components. • Quantification of 14 major components of Gumiganghwal-tang from human plasma samples. • Exploring the pharmacokinetic characteristics of Gumiganghwal-tang tablet in humans.

The purpose of this study was to compare pharmacokinetic (PK) parameters obtained using two newly developed assays, HPLC-UV and UPLC-ESI-MS/MS. Selection of assay and results obtained therefrom are very important in PK studies and can have a major impact on the PK-based clinical dose and usage settings. For this study, we developed two new methods that are most commonly used in biosample analysis and focused on PK parameters obtained from them. By HPLC-UV equipped with a Luna-C8 column using UV detector, cefprozil diastereomers were separated using water containing 2% (V/V) acetic acid and acetonitrile as a mobile phase. By UPLC-ESI-MS/MS equipped with a HALO-C18column, cefprozil diastereomers were separated using 0.5% (V/V) aqueous formic acid containing 5 mM ammonium-formate buffer and methanol as a mobile phase. Chromatograms showed high resolution, sensitivity, and selectivity without interference by plasma constituents. Both intra- and inter-day precisions (CV, %) were within 8.88% for HPLC-UV and UPLC-ESI-MS/MS. Accuracy of both methods was 95.67%–107.50%. These two analytical methods satisfied the criteria of international guidance and could be successfully applied to PK study. Comparison of PK parameters between two assays confirmed that there is a difference in the predicted minimum plasma concentrations at steady state, which may affect clinical dose and usage settings. Furthermore, we confirmed possible correlation between PK parameters and various biochemical parameters after oral administration of 1000 mg cefprozil to humans., Graphical abstract Image 1, Highlights • Development of UPLC-ESI-MS/MS and HPLC-UV methods for cefprozil diastereomers. • Comparison of PK parameters obtained using two newly developed assays. • Possible correlation between PK parameters and various biochemical parameters.

Novel formulations of donepezil (DNP)-loaded microspheres based on a bio-degradable polymer of poly(lactic-co-glycolic acid) (PLGA) with a one-month duration of effect were developed, aimed at reducing dosing frequency and adverse effects and improving patient adherence. The spherical and monodispersed DNP-loaded microspheres were precisely fabricated by the Inventage Lab Precision Particle Fabrication method (IVL-PPFM®) based on micro-electromechanical systems (MEMS) and microfluidic technology. The types of polymers and end-groups, the drug/polymer ratio (DPR), and the routes of administration for DNP were studied to ensure an effective concentration and desired duration. Laser-light particle size analysis and scanning electron microscopy were used to characterization. Also, non-clinical animal models of beagle dogs are used to optimize DNP formulations and evaluate their pharmacokinetic properties. The PK results showed that the DPR was a critical factor in determining the exposure level and duration of DNR release. Furthermore, the lactide ratio, which varied depending upon the type of polymer, determined the hydrophobic interaction and was also an important factor affecting the desired DNP release. Since DNP shows a large inter-species variation between dogs and humans, PK modeling and simulation of the reference drug (i.e., Aricept®) and DNP-loaded microspheres were used for formulation development to overcome and interpret these variations. In addition, the developed PK model was extrapolated to humans using the estimated PK parameter and published clinical pharmacology data for DNP. The predicted PK profile of the DNP-loaded microsphere in humans showed that the formulation with PLGA 7525A and the DPR of 1/9 could maintain drug concentration for a month and could control initial burst release. The data obtained from the study could be used as scientific evidence for decision-making in future formulation development.

The purpose of this study was to develop a sensitive method for quantifying cinnamic acid in human plasma using UPLC–ESI–MS/MS. Cinnamic acid was separated using water containing 0.005% (v/v) formic acid and acetonitrile as a mobile phase by gradient elution at a flow rate 0.2 mL/min, equipped with a HALO-C18 column (2.1 × 100 mm, 2.7 μm). Quantitation of this analysis was performed on a triple quadrupole mass spectrometer employing electrospray ionization technique, operating in multiple reaction monitoring negative ion mode. The mass transitions were m/z 146.8 → 103.0 for cinnamic acid, and 432.9 → 225.0 for geniposide as internal standard. Liquid–liquid extraction and protein precipitation with ethyl acetate–methanol-1.2% acetic acid (4/16/1, v/v/v) were used in the sample extraction. The chromatograms showed high resolution, sensitivity, and selectivity with no interference with plasma constituents. The calibration curves for cinnamic acid in human plasma were 0.1–500 ng/mL and displayed excellent linearity with correlation coefficients (r) greater than 0.99. Both the intra- and inter-day precisions (CV%) were within 3.88% for human plasma. The accuracy was 99.34–106.69% for human plasma. In vitro plasma protein binding of cinnamic acid was 64.26 ± 1.89 and 65.50 ± 1.78% for the spiked human plasma concentrations of 100 and 1000 ng/mL, respectively. The developed analytical method satisfied the criteria of international guidance and could be successfully applied to the pharmacokinetic study of cinnamic acid after oral administration of Socheongryong-tang tablets to humans.

Di-isobutyl phthalate (DiBP) is a substance used in the production of objects frequently used in human life. Mono-isobutyl phthalate (MiBP), a major in vivo metabolite of DiBP, is a biomarker for DiBP exposure assessment. Therefore, risk assessment studies on DiBP and MiBP, which have not yet been reported in detail, are needed. The aim of this study was to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for DiBP and MiBP in rats and extend this to human risk assessment based on human exposure. Pharmacokinetic studies were performed in male rats following the administration of 5–100 mg/kg DiBP, and these results were used for the development and validation of the PBPK model. In addition, the previous pharmacokinetic results in female rats following DiBP administration and the pharmacokinetic results in both males and females according to multiple exposures to DiBP were used to develop and validate the PBPK model. The metabolism of DiBP to MiBP in the body was very significant and rapid, and the biodistribution of MiBP was broad and major. Furthermore, the amount of MiBP in the body showed a correlation with DiBP exposure, and from this, a PBPK model was developed to evaluate the external exposure of DiBP from the internal exposure of MiBP. The predicted rat plasma, urine, fecal, and tissue concentrations using the developed PBPK model fitted well with the observed values. The established PBPK model for rats was extrapolated to a human PBPK model of DiBP and MiBP based on human physiological parameters and allometric scaling. The reference dose of 0.512 mg/kg/day of DiBP and external doses of 6.14–280.90 μg/kg/day DiBP for human risk assessment were estimated using Korean biomonitoring values. Valuable insight and approaches to assessing human health risks associated with DiBP exposure were provided by this study.

Osteoporosis is a common skeletal disease in post-menopausal women. Palmul-tang, an herbal medicine, has been treated for gynecological disease such as anemia, anorexia, anti-fatigue, unspecified menstruation and female infertility in East Asia. In this study, ameliorative effects of Palmul-tang soft extracts (PMT), a Korean Medicine, on osteoporosis were investigated. Ovariectomized (OVX) osteoporotic ICR mice were intragastrically administrated PMT for 4 weeks. The level of bone mineral density (BMD) was analyzed in bone tissues by dual X-ray absorptiometry. The bone medullary cavity and deposition of collagen were investigated by histological analysis. In addition, the BMP-2 signaling-related molecules, osteoblastic differentiation and formation markers, were determined in femoral tissues. The levels of BMD and bone mineral content were significantly increased in tibia, femurs and LV by treatment of PMT. PMT replenished bone marrow cavity and increased collagen deposition in bone marrow cells of femur. In addition, administration of PMT recovered serum ALP, bALP, osteocalcin and calcium levels in osteoporotic mice. Moreover, PMT treatment up-regulated the expressions of BMP-2, RUNX2 and OSX with its downstream factors, ALP, OPN and BSP-1, in the femoral tissues. Taken together, PMT restored the bone minerals and improvement of bone integrity by bone-forming BMP-2 signaling pathway. These results demonstrate that PMT could be an ameliorative agent for osteoporosis.

A controlled drug release formulation based on the subcutaneous injection of poly (lactic-co-glycolic acid) (PLGA) microspheres loaded with finasteride was prepared and evaluated for monthly delivery. After selection of biodegradable polymer and polymer-to-finasteride ratio, the formulation was characterized. Scanning electron microscopy (SEM) and laser-light particle size analysis were used to examine the morphology, surface structure, and particle size. High‑performance liquid chromatography (HPLC) was used to determine the drug loading, while liquid chromatography with tandem mass spectrometry (LC-MS/MS) was employed to analyze plasma finasteride concentrations. Results showed that the PLGA microspheres were spherical and of an appropriate size. The formulation stably releases the drug from the microspheres and the release sustained for a month without burst release, which was the desired duration. In vivo pharmacokinetic-pharmacodynamic (PK-PD) studies were conducted in beagle dogs through the administration of PROPECIA® (as a reference drug) per oral and subcutaneous injection of the long-acting injectable microsphere formulation (LAIF) loaded with five different doses of finasteride. From the acquired plasma data, PK-PD models for both PROPECIA®-administered group and LAIFs-injected groups were developed and validated. PK-PD profiles of both groups were predicted for up to one month. The predicted PK-PD profile of all LAIFs showed the achievability of monthly delivery and pharmacological effects without burst release, compared to the simulated PK-PD profile of PROPECIA®. According to the predicted PK-PD profiles, the formulation loaded with 16.8 mg of finasteride was determined to be the optimal dose. The data obtained from the PK-PD model could be used as the basis for the estimation of a first-in-human dose of the formulation.

Asarinin, β-eudesmol, and wogonin have common antiangiogenic activities and have the potential for use in chemotherapy. Besides, they are multivalent substances that are combined in various herbal medicines. The purpose of this study was to develop a method for simultaneous analysis of asarinin, β-eudesmol, and wogonin, which are representative pharmacological components of Asarum heterotropoides, Atractylodes lancea, and Scutellaria baicalensis, respectively, in rat biosamples using ultraperformance liquid chromatography-tandem mass spectrometry. The three components were separated using 5 mm aqueous ammonium acetate containing 0.1% formic acid and acetonitrile as a mobile phase, equipped with a KINETEX core-shell C18 column. The analysis was quantitated on a triple-quadrupole mass-spectrometer employing electrospray ionization, and operated in the multiple reaction monitoring mode. The chromatograms showed high resolution, sensitivity, and selectivity with no interference with plasma, urine, and feces constituents. The developed analytical method satisfied international guidance criteria and could be successfully applied to the pharmacokinetic (PK) studies evaluating oral bioavailability of asarinin, β-eudesmol, and wogonin after oral and intravenous administration and their urinary and fecal excretion ratios after oral administration to rats. Furthermore, the analysis was extended to PK studies following oral administration of Gumiganghwal-tang. This study was the first simultaneous analysis of the aforesaid three constituents in rat plasma, urine, and feces that also determined their PK parameters.

The purpose of this study was to develop a method for simultaneous analysis of aucubin, catalpol, and geniposide, which are representative iridoid glycoside constituents of Rehmannia glutinosa, in rat plasma, urine, and feces using hydrophilic interaction ultra high-performance liquid chromatography with tandem mass spectrometry. The three components were separated using 10 mmol/L aqueous ammonium formate containing 0.01% (v/v) formic acid and acetonitrile as a mobile phase by gradient elution at a flow rate of 0.2 mL/min, equipped with a Kinetex® HILIC column (50 × 2.1 mm, 2.6 μm). Quantitation of this analysis was performed on a triple quadrupole mass spectrometer employing electrospray ionization and operated in multiple reaction monitoring mode. The chromatograms showed high resolution, sensitivity, and selectivity with no interference with plasma constituents. In all three iridoid glycosides, both the intra- and interbatch precisions (coefficient of variation %) were less than 4.81%. The accuracy was 96.56-103.55% for aucubin, 95.23-106.21% for catalpol, and 94.50-104.16% for geniposide. The developed analytical method satisfied the criteria of international guidance and was successfully applied to pharmacokinetic studies including oral bioavailability of aucubin, catalpol, and geniposide, and their urinary and fecal excretion ratios after oral or intravenous administration to rats. The new method was also applied to measure plasma protein binding ratios in vitro.

Epinastine is an antiallergic drug with high selectivity for histamine receptors. It has been reported that 9,13b-dehydroepinastine is present as a metabolite in vivo in humans, but there was little information about their pharmacokinetics (PKs) in humans. Although several analytical methods have been reported for epinastine analysis in different matrices, none are available for its metabolite. Therefore, the purpose of this study was to develop an analytical method to simultaneously measure epinastine and its metabolite, 9,13b-dehydroepinastine, in human plasma samples using an ultra-performance liquid chromatography-tandem mass spectrometer. Analytes were separated on a C18 column. Quantification of this analysis was performed on a triple-quadrupole mass spectrometer. Chromatograms showed high sensitivity, selectivity, and resolution with no interference with plasma constituents. Calibration curves for both epinastine and 9,13b-dehydroepinastine in human plasma were 0.1-50 ng/ml and displayed excellent linearity with correlation coefficients (r2 ) >0.99. The developed analytical method satisfied the criteria of international guidance and was validated. The method could be successfully applied to pharmacokinetic studies of epinastine and, for the first time, the metabolite kinetics of epinastine to 9,13b-dehydroepinastine in humans after oral administration of 20 mg epinastine hydrochloride tablets. Our study is expected to be useful in future studies such as dosage settings and clinical pharmacotherapy.

The aim of this study was to explore the toxicokinetics of diisobutyl-phthalate (DiBP) and its major metabolite, monoisobutyl-phthalate (MiBP), by developing a UPLC-ESI-MS/MS method for simultaneously measuring DiBP and MiBP in rat plasma, urine, feces, and 11 different tissues. For the experiment, 0.1% (v/v) aqueous formic acid and acetonitrile mobile phase by gradient elution at a flow rate of 0.3 mL/min, equipped with a KINETEX core-shell C18-column (50 × 2.1 mm, 1.7 μm), was used to completely separate analytes. The mass transitions were m/z 279.1 → 149.0 for DiBP, 221.0 → 77.0 for MiBP, and 283.2 → 153.0 for DiBP-d4 as an internal standard. The developed assay had lower limits of quantification of 0.01 ng/mL for DiBP and 0.1 ng/mL for MiBP at all biological matrices. Toxicokinetics of DiBP were characterized by extensive distribution, short half-life, and high clearance. DiBP was rapidly metabolized to MiBP, with MiBP levels consistently exceeding the DiBP levels. Distribution of MiBP to tissues was considerable. The developed analytical method satisfied international criteria and was successfully applied to toxicokinetic studies after oral and intravenous administration of DiBP to rats. Findings of this study may be useful for evaluating the external exposure and toxic potential of DiBP and its metabolite in risk assessment.

Age-related macular degeneration (AMD) is wearing down of macula of retina, causing a blur or loss of vision in the center of the visual field. It can be categorized into dry or wet AMD. Until now, medical treatments for dry AMD have not been developed yet. The aim of this study was to evaluate pharmacokinetics (PKs) and tissue distribution of CK41016, a novel candidate for dry AMD, after intravenous (IV) or eye drop administration in rats and rabbits. In addition, a simple and sensitive bioanalytical method for CK41016 using ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) was developed. PK parameters were estimated by compartmental analysis using a WinNonlin&reg, software version 8.1 (a Certara&trade, company). A PK model of CK41016 was well-described by the two-compartment model. The tissue-to-plasma partition coefficient (Kp) of CK41016 was the highest in the vitreous humor of rats and the cornea of rabbits after eye drop administration. In addition, the Caco-2 cell transporter assay confirmed that CK41016 was not an active substrate for the efflux transporter. In summary, the PKs and tissue distribution of CK41016 were successfully evaluated and investigated whether this drug was a substrate of efflux transporters.

Due to the use of di-isobutyl-phthalate (DiBP) in the production of soft-polyvinyl chloride articles, it is currently a hazardous substance prevalent in human daily life. However, reports on DiBP's toxicokinetics are still very scarce. And no studies have been reported on gender differences in DiBP toxicokinetics. Therefore, this study was conducted in accordance with these research needs. DiBP of 100 mg/kg has been exposed to male and female rats single or multiple times. DiBP and its major metabolite, mono-isobutyl-phthalate (MiBP), were quantified from various biological samples obtained from rats administered with DiBP. Based on these results, several toxicokinetic parameters were estimated. Toxicokinetic results between genders were compared, and from this, existence and extent of gender differences in DiBP's toxicokinetics were explored. Investigation of presence and extent of subacute toxicity in male and female rats following multiple exposures to DiBP were also conducted. This study provided comprehensive information on DiBP toxicity and gender differences that have not been reported in detail. Results of these studies imply that subacute toxicity in liver, kidney, lung, and testis of rats at 100 mg/kg of DiBP is modest and that there is little difference in toxicokinetics between genders. And in both male and female rats, the metabolism of DiBP (to MiBP) was significant, and excretion of MiBP into urine was a major indicator of DiBP exposure.

The aim of this study was to compare UPLC-MS/MS and HPLC-UV methods for the determination of zaltoprofen in human plasma. In HPLC-UV, zaltoprofen was separated using 1% (v/v) aqueous acetic acid (pH 2.2) and acetonitrile (ACN) mixed with methanol as a mobile phase (1% aqueous acetic acid/ACN/methanol, 36/60/4, v/v/v) by isocratic elution at a flow rate of 1.0 mL/min with a Zorbax ODS column (250 × 4.6 mm, 5 µm). Quantification of zaltoprofen was performed using a UV detector (330 nm). In UPLC-MS/MS, zaltoprofen was separated using 0.1% (v/v) aqueous formic acid containing 0.5% (v/v) of 10 mM ammonium formate (pH 3.2) buffer (pH 2.3) and ACN as a mobile phase by gradient elution at a flow rate of 0.3 mL/min with a KINETEX core–shell C18 column (50 × 2.1 mm, 1.7 µm). Quantitation of UPLC-MS/MS was performed on a triple quadrupole mass spectrometer using electrospray ionization, operating in the multiple reaction monitoring positive ion mode. The calibration ranges for zaltoprofen in HPLC-UV and UPLC-MS/MS were 0.05–20 and 0.005–10 µg/mL, respectively. The developed methods satisfied the international guidance criteria and can be successfully applied to pharmacokinetic study of an 80 mg zaltoprofen tablet after oral administration to humans.

The purpose of this study was to develop a method for simultaneous analysis of schizandrin, ephedrine, paeoniflorin, and cinnamic acid as constituents of Socheongryong-tang tablet in human plasma using UPLC-MS/MS. These four components were separated using water containing 0.01% formic acid and methanol as a mobile phase by gradient elution at a flow rate of 0.3 mL/min with a HALO-C18 column (2.1 mm × 100 mm, 2.7 μm particle size). Quantitation was performed on a triple quadrupole mass spectrometer employing electrospray ionization technique operated in multiple reaction monitoring mode. Mass transitions were m/z 432.9 → 384.1 for schizandrin, 165.8 → 148.1 for ephedrine, 525.0 → 449.2 for paeoniflorin, 146.8 → 102.9 for cinnamic acid, and 340.0 → 324.0 for papaverine as internal standard. Liquid-liquid extraction and protein precipitation with ethyl acetate-methanol (1:2, v/v) were used to obtain these four components. Chromatograms showed high resolution, sensitivity, and selectivity without interference by plasma constituents. Calibration curves of schizandrin, ephedrine, paeoniflorin, and cinnamic acid in human plasma ranged from 0.02 to 8 ng/mL, 0.5 to 200 ng/mL, 0.2 to 80 ng/mL, and 1 to 400 ng/mL, respectively. Calibration curves of each analyte displayed excellent linearity, with correlation coefficients > 0.99. For all four components, both intra- and inter-day precisions (CV%) were

Objective This study was conducted to determine whether a fixed-dose combination (FDC) tablet of repaglinide/metformin (2/500 mg) is equivalent to coadministration of equivalent doses of individual (EDI) tablets of repaglinide (2 mg) and metformin (500 mg) in healthy Korean male subjects. Materials and methods This study was conducted as an open-label, randomized, single-dose, two-period, two-sequence crossover design in 50 healthy Korean male subjects who received an FDC tablet or EDI tablets. Plasma concentrations of repaglinide and metformin were determined for up to 24 hours using a validated UPLC-MS/MS method. Bioequivalence was assessed according to current guidelines issued by the U.S. Food and Drug Administration (FDA) and Korean legislation. Tolerability was also evaluated throughout the study via subject interview, vital signs, and blood sampling. Results Point estimates (90% CIs) for AUC0-t, AUC0-∞, and Cmax based on EDI tablets were 110.07 (102.25 - 118.49), 109.90 (101.70 - 118.39), and 112.60 (101.49 - 124.85), respectively, for repaglinide. They were 95.18 (89.62 - 101.05), 95.00 (89.74 - 100.65), and 98.44 (92.72 - 104.50), respectively, for metformin. These results satisfied the bioequivalence criteria of 80.00 - 125.00% proposed by the FDA and Korean legislation. Conclusion Results of pharmacokinetic analysis suggested that repaglinide and metformin in FDC tablets were bioequivalent to EDI tablets of repaglinide (2 mg) and metformin (500 mg) in healthy Korean male subjects. Both formulations appeared to be well tolerated. .

Fixed dose combination (FDC) of valsartan (VAL) and hydrochlorothiazide (HCT) or VAL and amlodipine (AML) has been available in many countries for the treatment of hypertension. Due to drug-drug interaction potentials, in the current study we aimed to evaluate potent effects of HCT and AML on pharmacokinetics (PKs) of VAL when they are orally co-administered as FDC (VAL/HCT at 80/12.5 mg or 160/12.5 mg; and VAL/AML at 160/5 mg or 160/10 mg) products in healthy Korean subjects. Population pharmacokinetic (PK) modeling and analysis were performed by the nonlinear mixed-effects modeling software. PKs of VAL was described by two-compartment disposition model, first-order elimination, four-sequential first-order absorption model, correlation between apparent clearances and volumes of distribution, and lag time. For all FDCs, there were no statistically significant differences in both maximum concentration and areas under the concentration-time curves (AUCs) of VAL in comparison to those when administered VAL alone, except the combination of VAL/AML at 160/10 mg, where AUC0–∞ increased by 11.8% in mean and 6.86% in median. In addition, there was an increasing trend in time to reach peak (Tmax) of VAL in FDCs, where it was increased by 0.22–0.34 h in mean and 0.40–0.44 h in median, except the combination of VAL/HCT at 160/12.5 mg. However, these differences in AUC0–∞ and Tmax might not be considered as clinically important. In conclusion, HCT or AML has no potent effect on PKs of VAL when they are co-administered as FDC products. No dose adjustment for VAL is recommended when co-administered with HCT or AML.

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger approved for the treatment of amyotrophic lateral sclerosis, a fatal neuromuscular disease. Edaravone is administered as an intravenous infusion over 60 min for several treatment cycles. To ease the burden of patients and caregivers, the oral formulation of edaravone has been developed. The purpose of this study was to evaluate pharmacokinetics and tissue distribution of TEJ-1704, an edaravone oral prodrug, in male Sprague Dawley rats and beagle dogs. Animal experiments were conducted using Sprague Dawley rats and beagle dogs to evaluate pharmacokinetics, tissue distribution, and excretion of TEJ-1704. Blood, tissues, cerebrospinal fluid, urine, and feces samples were collected at designated sampling time after intravenous (IV) or oral (PO) administration of edaravone or TEJ-1704. A modified bioanalysis method was developed to quantify edaravone in samples including plasma, tissues, cerebrospinal fluid, urine, and feces. The bioanalysis method was validated and successfully applied to pharmacokinetics, tissue distribution, and excretion studies of the novel edaravone prodrug. Although plasma Cmax of TEJ-1704 was low, groups administered with TEJ-1704 had high AUCinf, suggesting continuous metabolism of TEJ-1704 into edaravone. Groups treated with TEJ-1704 also showed lower CSF distribution than the control groups. After the administration of TEJ-1704, the majority of edaravone was distributed to the heart, lung, and kidney. It was excreted equally via urine and feces. The pharmacokinetics, tissue distribution, and excretion of TEJ-1704, a novel edaravone oral prodrug, were successfully characterized. Additional studies are needed to fully understand the difference between TEJ-1704 and edaravone and determine the potency of TEJ-1704.

Perfluorohexanesulfonate (PFHxS), which belongs to the group of perfluoroalkyl and polyfluoroalkyl substances (PFASs), has been extensively used in industry and subsequently detected in the environment. Its use may be problematic, as PFHxS is known to induce neuronal cell death, and has been associated with early onset menopause in women and with attention deficit/hyperactivity disorder. Due to these impending issues, the aim of this study is to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for PFHxS in male and female rats, and apply this to a human health risk assessment. We conducted this study in vivo after the oral or intravenous administration of PFHxS in male (dose of 10 mg/kg) and female rats (dose of 0.5-10 mg/kg). The biological samples consisted of plasma, nine tissues, urine, and feces. We analyzed the sample using ultra-liquid chromatography coupled tandem mass spectrometry (UPLC-MS/MS). Our findings showed the tissue-plasma partition coefficients for PFHxS were highest in the liver. The predicted rat plasma and tissue concentrations using a simulation fitted well with the observed values. We extrapolated the PBPK model in male and female rats to a human PBPK model of PFHxS based on human physiological parameters. The reference doses of 0.711 µg/kg/day (male) and 0.159 µg/kg/day (female) and external doses of 0.007 µg/kg/day (male) and 0.006 µg/kg/day (female) for human risk assessment were estimated using Korean biomonitoring values. This study provides valuable insight into human health risk assessment regarding PFHxS exposure.

The aim of this study was to develop an analytical method to simultaneously analyze schizandrin, schizandrol B, and gomisin N lignans in human plasma using ultra high performance liquid chromatography with tandem mass spectrometry. The three lignans were separated using a mobile phase of water and acetonitrile containing 0.02% acetic acid equipped with a Kinetex C18 column (2.1 mm × 50 mm, 1.7 μm). This analysis was achieved by multiple reaction monitoring mode in an electrospray interface. The mass transitions were m/z 433.1→384.0 for schizandrin, 398.8→367.8 for schizandrol B, and 400.6→299.8 for gomisin N. Liquid-liquid extraction with methyl tert-butyl ether was used to obtain the three lignans. The chromatograms showed high resolution, sensitivity, and selectivity with no interference with plasma constituents. The calibration curves for the three lignans in human plasma were 0.05-50 ng/mL and displayed excellent linearity with correlation coefficients greater than 0.99. Precision for all three lignans was within 11.23%. The accuracy was 88.3-99.0% for schizandrin, 90.6-103.4% for schizandrol B, and 90.2-103.5% for gomisin N. The developed simultaneous analytical method satisfied the criteria of international guidance and could be successfully applied to the pharmacokinetic study of three lignans after oral administration of Schisandrae Fructus extract powder to humans.

In this study, the population pharmacokinetic (PK) analysis of rebamipide (Reba) in healthy male Korean subjects was analyzed using the nonlinear mixed effects modeling method. The possible effects of physiological covariates and the multidrug resistance (MDR1) gene 3435C>T polymorphism on PK parameters were also investigated. Data were collected from a bioequivalence study, in which 26 subjects who participated in the study were administered a single oral dose of 100 mg Reba; only data from the reference formulation were used. Reba showed a relatively large inter-individual variability (from 2.6- to 3.3-fold) in the PK parameters with double peaks or the concentration plateau after the peak concentration in its serum concentration–time profiles. The population PKs of Reba was best described by a one-compartment model with three fraction absorption processes followed a single Weibull-type function and two first-order kinetics, and lag times. The study suggests that the efflux transporter MDR1 3435C>T allele affects the substantial inter-individual variability in the absorption of Reba according to genetic polymorphism. A significant difference was found in the absorption rate ka 1 among the MDR1 3435C>T genotype groups (P T and body mass index as covariates for ka 1 exerted a more significant effect (P