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Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and paracetamol can be administered off-label to cattle. Since the use of these veterinary medicines in cattle may pose a public health risk after meat consumption, it is important to translate measured concentrations in urine and tissues into concentrations in meat for human consumption. A generic physiologically-based kinetic (PBK) model for cattle can enable this translation. In this work, a beef cattle PBK model was applied to calculate the relationships between concentrations in different bovine tissues and those were compared to measured concentrations in different matrices. Sixty-seven kidney samples, the corresponding urine and meat samples, and available 19 serum samples were analysed. Overall, 70% of the PBK model predictions are within a 2-fold factor and relationships for kidney/meat, urine/meat, and plasma/meat ratios were established. The conversions of measured kidney concentrations into meat concentrations were mostly within a factor two, while those based on plasma and urine were underpredicted. Based on these ratios, plasma and urine could be used as an appropriate surrogate matrix for a fast, simple in vivo sample screening test under field conditions, such as in local farms and slaughterhouses, to predict a maximum residue level exceedance in meat, reducing the number of test samples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Although research on the mechanism and control of pain and inflammation in fish has increased in recent years, the use of analgesic drugs is limited due to the lack of pharmacological information about analgesic drugs. Tolfenamic acid is a non-steroidal anti-inflammatory drug and can be used in fish due to its low side effect profile and superior pharmacokinetic properties., Objectives: The pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid were investigated following single intravascular (IV), intramuscular (IM) and oral administration of 2 mg/kg in rainbow trout at 13 ± 0.5°C., Methods: The experiment was carried out on a total of 234 rainbow trout (Oncorhynchus mykiss). Tolfenamic acid was administered to fish via IV, IM and oral route at a dose of 2 mg/kg. Blood samples were taken at 13 different sampling times until the 72 h after drug administration. The plasma concentrations of tolfenamic acid were quantified using high pressure liquid chromatography-ultraviolet (UV) and pharmacokinetic parameters were assessed using non-compartmental analysis., Results: The elimination half-life (t 1/2ʎz ) of tolfenamic acid for IV, IM and oral routes was 3.47, 6.75 and 9.19 h, respectively. For the IV route, the volume of distribution at a steady state and total body clearance of tolfenamic acid were 0.09 L/kg and 0.03 L/h/kg, respectively. The peak plasma concentration and bioavailability for IM and oral administration were 8.82 and 1.24 µg/mL, and 78.45% and 21.48%, respectively. The mean plasma protein binding ratio of tolfenamic acid in rainbow trout was 99.48% and was not concentration dependent., Conclusions: While IM route, which exhibits both the high plasma concentration and bioavailability, can be used in rainbow trout, oral route is not recommended due to low plasma concentration and bioavailability. However, there is a need to demonstrate the pharmacodynamic activity of tolfenamic acid in rainbow trout., (© 2024 The Author(s). Veterinary Medicine and Science published by John Wiley & Sons Ltd.)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs that can cause liver toxicity. The aim of this study was to integrate bioanalytical and population pharmacokinetic (PopPK) assay to rapidly screen and quantify the concentrations of NSAIDs in plasma and monitor clinical safety. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous quantification of acetaminophen (APAP), flurbiprofen (FLB), aspirin (ASP), and ibuprofen (IBP), four commonly used NSAIDs. The PopPK model of the signature toxicant was analyzed based on the published literature. The LC-MS/MS method was successfully validated and applied to determine NSAID concentrations in patient plasma samples. APAP, ASP, and IBP data were best fitted using a one-compartment model, and FLB data were best fitted using a two-compartment model. Bootstrapping and visual predictive checks suggested that a robust and reliable pharmacokinetic model was developed. A fast, simple, and sensitive LC-MS/MS method was developed and validated for determining APAP, FLB, ASP, and IBP in human plasma. Combined with the PopPK model, this method was applied to rapidly analyze the concentrations of NSAIDs in clinical samples from patients presenting to the emergency department with acute liver dysfunction and monitored NSAIDs clinical safety., (© 2024 John Wiley & Sons Ltd.)

Objective: To evaluate the effects of aging on phenylbutazone (PBZ) disposition in older horses (≥ 25 years old) compared to young adults (4 to 10 years old) by characterizing the pharmacokinetic profile of PBZ and its active metabolite, oxyphenbutazone (OPBZ), following a 2.2-mg/kg dose, IV. We hypothesized that the disposition of PBZ will be affected by age., Animals: 16 healthy horses (8 young adults aged 4 to 10 years and 8 geriatric horses ≥ 25 years old)., Methods: Horses were administered a single 2.2-mg/kg PBZ dose, IV. Plasma samples were collected at designated time points and frozen at -80 °C until assayed using liquid chromatography-tandem mass spectrometry. Pharmacokinetic analyses were performed using Phoenix WinNonlin, version 8.0 (Certara). Both clinical and pharmacokinetic data were compared between age groups using independent samples t tests, with P < .05 considered significant., Results: Baseline characteristics did not differ between groups, with the exception of age, weight, and plasma total solids. Plasma concentrations of PBZ were best described by a two-compartment model. The maximum plasma concentration of OPBZ was reached at 5 hours for both age groups, and the metabolite-to-parent-drug area-under-the-curve ratios were approximately 20% for both groups. None of the pharmacokinetic parameters of PBZ or its metabolite, OPBZ, differed significantly between age groups., Clinical Relevance: The hypothesis was rejected as there was no significant difference in PBZ disposition in young-adult horses compared to geriatric horses. Our data do not support the need for dose adjustments of PBZ in clinically healthy geriatric horses.

Objective: This study compared the pharmacokinetics, safety and bioequivalence (BE) of generic and original apremilast tablets in healthy Chinese subjects under fasting and postprandial conditions, providing sufficient evidence for abbreviated new drug application., Methods: A randomized, open-label, two-formulation, single-dose, two-period crossover pharmacokinetic study was performed. Thirty-two eligible healthy Chinese subjects were enrolled in fasting and postprandial studies, respectively. In each trial, subjects received a single 30-mg dose of the test or reference apremilast tablet, followed by a 7-day washout interval between periods. Serial blood samples were obtained for up to 48 h post-intake in each period, and the plasma concentrations of apremilast were determined by a validated method. The primary pharmacokinetic (PK) parameters, including the maximum plasma concentration (C max ), the areas under the plasma concentration-time curve (AUC 0-t , AUC 0-∞ ), were calculated using the non-compartmental method. The geometric mean ratios of the two formulations and the corresponding 90% confidence intervals (CIs) were acquired for bioequivalence analysis. The safety of both formulations was also evaluated., Results: Under fasting and postprandial states, the PK parameters of the test drug were similar to those of the reference drug. The 90% CIs of the geometric mean ratios of the test to reference formulations were 94.09-103.44% for C max , 94.05-103.51% for AUC 0-t , and 94.56-103.86% for AUC 0-∞ under fasting conditions, and 99.18-112.48% for C max , 98.79-106.02% for AUC 0-t , and 98.95-105.89% for AUC 0-∞ under postprandial conditions, all of which were within the bioequivalence range of 80.00-125.00%. Both formulations were well tolerated, and no serious adverse events occurred during the study., Conclusion: The trial confirmed that the PK parameters of the generic and original apremilast tablets were bioequivalent in healthy Chinese subjects under fasting and postprandial states, which met the predetermined regulatory standards. Both formulations were safe and well tolerated., Clinical Trial Registration: chinaDrugtrials.org.cn, identifier CTR20191056 (July 30, 2019); chictr.org.cn, identifier ChiCTR2300076806 (October 19, 2023)., Competing Interests: The authors declare that there are no conflicts of interest in this study., (© 2024 Bai et al.)

The integration of pain management in veterinary practice, driven by heightened animal welfare concerns, extends to avian species where subtle and nonspecific behavioral signs pose challenges. Given that safety concerns with classical NSAIDs highlight the need for more targeted alternatives in birds, this study explores the pharmacokinetic (PK) properties of Deracoxib (DX), a COX-2 selective NSAID approved for use in dogs, following a single oral administration in geese. Six healthy female geese received 4 mg/kg DX. Blood was drawn from the left wing vein to heparinized tubes at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, and 24 h. Plasma DX concentrations were measured using HPLC coupled to an UV detector, and the data were pharmacokinetically analyzed using PKanalix™ software in a non-compartmental approach. The results indicated a terminal half-life of 6.3 h and a T max of 1 h, with no observed adverse effects. While refraining from claiming absolute safety based on a single dose, it is worth highlighting that further safety studies for DX in geese are warranted, suggesting a possibility for intermittent use. In addition, drawing conclusions on efficacy and suitability awaits further research, particularly in understanding COX-2 selectivity and protein binding characteristics specific to geese., (© 2024 John Wiley & Sons Ltd.)

The aim of this study is to determine the pharmacokinetic change after intravenous administration of meloxicam at doses of 0.5, 1 and 2 mg/kg to sheep. The study was carried out on six Akkaraman sheep. Meloxicam was administered intravenously to each sheep at 0.5, 1, and 2 mg/kg doses in a longitudinal pharmacokinetic design with a 15-day washout period. Plasma concentrations of meloxicam were determined using the high performance liquid chromatography-ultraviolet, and pharmacokinetic parameters were evaluated by non-compartmental analysis. Meloxicam was detected up to 48 h in the 0.5 mg/kg dose and up to 96 h in the 1 and 2 mg/kg doses. As the dose increased from 0.5 to 2 mg/kg, terminal elimination half-life, and dose normalized area under the concentration versus time curve increased and total clearance decreased. Compared to the 1 mg/kg dose, it was determined that V dss decreased and C 0.083h increased in the 2 mg/kg dose. Meloxicam provided the therapeutic concentration of >0.39 μg/mL reported in other species for 12, 48 and 96 h at 0.5, 1 and 2 mg/kg doses, respectively. These results show that meloxicam exhibits non-linear pharmacokinetics and will achieve unpredictable plasma concentrations when administered IV for a rapid effect at dose of ≥1 mg/kg in sheep., (© 2023 John Wiley & Sons Ltd.)

Experimental design is a significant tool for optimization and validation for the development of HPLC methods to determine API in both human serum and pharmaceutical formulations. In this study, RP-HPLC method is developed and validated for the simultaneous determination of moxifloxacin and NSAIDs. In this experiment, Purospher STAR C18 column with optimum assay conditions (10:90, v/v, water: methanol, pH 2.75) used as mobile phase having flow rate of 1.5mL min -1 and screened at 240 nm. The experimental results exhibit reliability through accuracy (98-102%), precision (0.011-1.85%) and linearity (R 2 >0.999) in range of 0.15-40μgmL -1 . The LOD and LOQ limits for moxifloxacin and NSAIDs are found to be 0.015 and 0.046 μgmL -1 respectively. The significant outcomes conclude that the developed method for assay is effectively suitable to human serum and pharmaceutical formulations and there is no interference from excipients of tablets and serum. The proposed method is useful for drug-interaction and investigation of moxifloxacin with NSAIDs.

In this research, the Cu-based metal-organic framework (MOF-199) was fabricated and coated on the stainless steel mesh as substrates through sol-gel procedure. Then the coated substrates were placed in a small column known as solid-phase extraction cartridge. The SPE based coated stainless steel mesh coupled with high-performance liquid chromatography-UV detector (HPLC-UV) was used for the fast extraction, and quantification of non-steroidal anti-inflammatory drugs (NSAIDs) from human plasma and water samples. To find optimum extraction conditions, the impacts of effective parameters on analytical performance like sample pH, sample volume, type, and volume of desorption solvent were optimized. At the optimized conditions, calibration graphs of analytes were linear in the concentration range of 0.03-300 ng mL -1 for water samples, and 0.1-200 ng mL -1 for plasma samples. The correlation coefficients were in the range of 0.9938 to 0.9989. Also, the limits of detection (LODs) were from 0.01 to 0.02 ng mL -1 for water samples and 0.03 to 0.1 ng mL -1 for plasma samples. The cartridge repeatability was studied at different values, and the relative standard deviations (RSDs%) were achieved between 3.5 and 5.1%. Consequently, this procedure was successfully used in the extraction and detection of NSAIDs in real water and plasma samples with relative recoveries ranged from 93.6 to 99.6%., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

For the quantification of flurbiprofen in rat plasma, a simple UPLC-MS/MS method with high sensitivity and short retention time for flurbiprofen was developed and validated using specific parameters. Etodolac was used as internal standard. The transitions (precursor to the product) of flurbiprofen and internal standard were obtained using the electrospray ionization in the negative ion multiple reaction monitoring mode, 243.2 → 199.2, 286.2 → 212.1, respectively. For chromatographic separation, C18 column was used for the stationary phase and gradient elution was used for the mobile phase. This mobile phase consisted of a methanol (A) and a 5 mM ammonium formate solution (B), which varied at a flow rate of 0.4 mL/min. For flurbiprofen, LLOQ was determined as 5 ng/mL. Quantification of flurbiprofen in the rat plasma with a linear calibration curve of 5-5000 ng/mL (r > 0.9991 for plasma) is possible with a retention time of 1.89 min. The total analysis time of the method was 3 min. The proposed method was validated. The intraday and inter-day precision (RSD%) and accuracy (RE%) were within 10% in all cases for flurbiprofen. The stability of flurbiprofen was evaluated under conditions such as short-term, long-term, autosampler and freeze/thaw. After method validation, flurbiprofen was succesfully quantified in real rat plasma samples., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Establishing bioequivalence (BE) for dermatological drug products by conducting comparative clinical end point studies can be costly and the studies may not be sufficiently sensitive to detect certain formulation differences. Quantitative methods and modeling, such as physiologically-based pharmacokinetic (PBPK) modeling, can support alternative BE approaches with reduced or no human testing. To enable PBPK modeling for regulatory decision making, models should be sufficiently verified and validated (V&V) for the intended purpose. This report illustrates the US Food and Drug Administration (FDA) approval of a generic diclofenac sodium topical gel that was based on a totality of evidence, including qualitative and quantitative sameness and physical and structural similarity to the reference product, an in vivo BE study with PK end points, and, more importantly, for the purposes of this report, a virtual BE assessment leveraging dermal PBPK modeling and simulation instead of a comparative clinical end point study in patients. The modeling approach characterized the relationship between systemic (plasma) and local (skin and synovial fluid) diclofenac exposure and demonstrated BE between the generic and reference products at the presumed site of action. Based on the fit-for-purpose modeling principle, the V&V process involved assessing observed data of diclofenac concentrations in skin tissues and plasma, and the overall performance of the modeling platform for relevant products. Using this case as an example, this report provides current scientific considerations on good practices for model V&V and the establishment of BE for dermatological drug products when leveraging PBPK modeling and simulation for regulatory decision making., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Flurbiprofen is a non-steroidal anti-inflammatory drug. We evaluated the bioequivalence of a new formulation of flurbiprofen axetil for injection and the reference drug ROPION (another kind of flurbiprofen axetil injection marketed for use) in healthy Chinese subjects. This is a single-centre, randomized, open-label, single-dose, two period crossover bioequivalence study. Each subject received a single intravenous injection at the dose of 50 mg under fasting. The drug was dissolved in 100 mL normal saline, and the injection was completed in 15 minutes. There was a 7-day washout period between the two administrations. The plasma concentrations of flurbiprofen were measured by LC-MS/MS, and descriptive statistics were used to describe the safety outcomes including adverse events (AEs) and adverse drug reactions (ADRs). Twenty-four subjects were enrolled in this study. Mean values of primary PK parameters (T max , C max , AUC 0-t , AUC 0-∞ , λ z , T 1/2 ) were similar (P > 0.05). T max for both products is 0.3 hours. The 90% confidence intervals (CIs) for peak concentration C max ranged between 96.87% and 100.42%, and the area under curve AUC 0-t and AUC 0-∞ ranged between 99.09% and 104.29% and 98.97% and 104.29%, respectively. The 90% CIs for the geometric means and ratios of primary PK endpoints of flurbiprofen axetil injection to reference drug ranged between 98.97% and 104.29%. The adverse event rate of the test product was 8.3% and no serious adverse events (SAE) occurred in this clinical study. We concluded that the test product and the reference drug were bioequivalent and the safety was high in healthy Chinese subjects., (© 2021 John Wiley & Sons Australia, Ltd.)

Background: This study was to investigate the value of 10 serum inflammatory cytokines for predicting clinical response to celecoxib in ankylosing spondylitis (AS) patients., Methods: Totally, 103 active AS patients who underwent celecoxib treatment for 12 weeks were enrolled. Then, pre-treatment serum TNF-α, IL-1β, IL-6, IL-8, IL-17A, IL-21, IL-23, IL-32, ICAM-1, and VEGF were detected by enzyme-linked immunosorbent assay. Besides, the ASAS 20 response was assessed at week 2 (W2), week 6 (W6), and week 12 (W12). Based on the ASAS 20 response at W12, patients were divided into responders and non-responders., Results: After celecoxib treatment, 53 (51.3%), 58 (56.3%), and 60 (58.3%) patients achieved ASAS 20 response at W2, W6, and W12, respectively. Furthermore, IL-1β (P = 0.019), IL-6 (P = 0.004), and IL-17A (P = 0.007) levels were higher, while TNF-α (P = 0.086), IL-8 (P = 0.143), IL-21 (P = 0.687), IL-23 (P = 0.329), IL-32 (P = 0.216), ICAM-1 (P = 0.119), and VEGF (P = 0.732) levels were similar in responders compared with non-responders. Subsequent multivariate logistic regression analysis revealed that among these inflammatory cytokines, only IL-6 (P = 0.019) independently predicted higher ASAS 20 response to celecoxib at W12, and it had a fair value for predicting ASAS 20 response to celecoxib at W12 (area under the curve: 0.666, 95% confidence interval: 0.561-0.771) by receiver-operating characteristic curve analysis., Conclusion: Serum IL-1β, IL-6, and IL-17A serve as indicators for predicting clinical response to celecoxib in AS patients, which may assist with the optimization of personalized treatment.

The objective of this study was to determine the pharmacokinetics of a single dose of meloxicam administered subcutaneously (SQ) to three species of sea turtles: loggerheads ( Caretta caretta ), Kemp's ridley ( Lepidochelys kempii ), and greens ( Chelonia mydas ). A dose of 1 mg/kg was given to the Kemp's ridleys and greens, whereas the loggerheads received 2 mg/kg. After SQ administration, the half-life (t1/2) of meloxicam administered at 1 mg/kg in the Kemp's ridleys was 5.51 hr but could not be determined in the greens. The half-life of meloxicam administered at 2 mg/kg in the loggerheads was 2.99 hr. The maximum concentration (Cmax) for meloxicam after SQ administration at 1 mg/kg in the Kemp's ridleys was 6.76 µg/ml and in the greens was 9.35 µg/ml. The Cmax in loggerheads for meloxicam after SQ administration at 2 mg/kg was 3.63 µg/mL. Meloxicam administered SQ at a dose of 1 mg/kg to the Kemp's ridley and greens provided measurable plasma concentrations of meloxicam for 48 and 120 hr, respectively, with no adverse side effects. In loggerheads, meloxicam administered SQ at a dose of 2 mg/kg provided measurable plasma levels of meloxicam for only 24 hr. Plasma levels of meloxicam of greater than 0.5 µg/ml are considered to be therapeutic in humans. Results suggested that administration of meloxicam SQ at 1 mg/kg in Kemp's ridleys and greens would result in plasma concentrations greater than 0.5 µg/ml for 12 and 120 hr, respectively. The administration of 2 mg/kg meloxicam to loggerhead turtles resulted in plasma concentrations greater than 0.5 µg/ml for only 4 hr.

Background: Ibuprofenamine hydrochloride spray is novel transdermal nonsteroidal anti-inflammatory drugs (NSAIDs), under clinical development for the treatment of Rheumatoid Arthritis and Osteoarthritis as a novel transdermal drug., Methods: A single and multiple ascending dose study investigated the safety, tolerability and pharmacokinetics of ibuprofenamine hydrochloride in healthy Chinese subjects. A total of 34 subjects (single-dose study: 34 subjects and multiple-dose study: 20 subjects) were involved in the trial. In the single-dose study, subjects were assigned to one of the four groups received 35, 70, 140, 280 mg. In the 70 mg and 140 mg treatment groups, subjects received one dose on the first day and twice a day from day 6 to 12. The starting dose was determined considering the no observed adverse effect level based on preclinical studies, and the dose escalations in subsequent cohorts were decided based on safety, tolerability, and pharmacokinetic data from previous dose cohorts., Results: After a single dose, both ibuprofenamine and ibuprofen plasma exposure showed a more than dose-proportional increase across a dose range of 35-280 mg. After multiple dosing, both ibuprofenamine and ibuprofen steady-state exposure increased obviously more than dose-proportional manner across the evaluated dose range (twice a day for 7 days) resulted in obvious accumulation. Single or multiple doses of ibuprofenamine hydrochloride were generally well tolerated and no obvious skin irritation was observed., Conclusion: Ibuprofenamine hydrochloride exhibited a safety and pharmacokinetic profile that supports its future investigation as a potential therapeutic for Rheumatoid Arthritis and Osteoarthritis., Competing Interests: The authors declare that they have no conflicts of interest., (© 2021 Xie et al.)

A low cost-effective and simple synthesis method was adopted to acquire three-dimensional flower-like structure Fe 3 O 4 /C that has large specific area, suitable pore structure and sufficient saturation magnetism. The obtained Fe 3 O 4 /C exhibits outstanding preconcentration ability and was applied to extracting non-steroidal anti-inflammatory drugs from complex environmental and biological samples. The parameters of magnetic solid-phase extraction were optimized by univariate and multivariate methods (Box-Behnken design). The high degree of linearity from 2.5 to 1000.0 ng mL -1 (R 2  ≥ 0.9976), the limits of detection from 0.25 to 0.5 ng mL - 1 (S/N = 3), and the limits of quantitation from 1.0 to 2.0 ng mL - 1 (S/N = 10) were yielded by adopting this novel method after the optimization. Moreover, the recoveries of non-steroidal anti-inflammatory drugs from 89.6 to 107.0% were acquired in spiked plasma, urine and lake samples. In addition, the adsorption of non-steroidal anti-inflammatory drugs on Fe 3 O 4 /C was explored by adsorption isotherms and kinetic studies. Furthermore, the adsorption mechanism for non-steroidal anti-inflammatory drugs by Fe 3 O 4 /C was proposed, which was hydrogen bonding and π-π interaction between non-steroidal anti-inflammatory drugs and Fe 3 O 4 /C. Graphical abstract.

Flunixin meglumine is the most commonly used nonsteroidal anti-inflammatory drug used to treat elephants; however, no pharmacokinetic study for flunixin has yet been conducted in these species, and dosages used range widely. Pharmacokinetic parameters of flunixin were determined in African ( Loxodonta africana ) and Asian ( Elephas maximus ) elephants after single-dose oral administration of 0.8 and 1.5 mg/kg flunixin paste in each species. Elephant compliance to oral administration of banamine was occasionally challenging, especially among older, female African elephants. After administration of 0.8 mg/kg flunixin, mean serum concentrations peaked in approximately 1.3 hr at 2.1 ± 0.8 µg/ml for Asian ( n = 8) and 2.8 hr at 2.5 ± 0.7 µg/ml for African ( n = 8) elephants. Dosages of 1.5 mg/kg flunixin resulted in mean serum concentration peaks of 7.2 ± 1.5 µg/ml in Asian elephants ( n = 7) and 4.4 ± 0.7 µg/ml in African elephants ( n = 6). However, multiple-dose trials using 1.1 mg/kg flunixin resulted in peak serum concentrations that were again less in Asian than African elephants (2.7 µg/ml versus 4.4 µg/ml, respectively). Asian elephants consistently had lower time to maximal concentration, greater area under the curve, and longer mean residence times compared with African elephants. In other species, flunixin is excreted unchanged primarily via hepatic routes with small amounts in the urine. Asian elephants may engage in some level of enterohepatic recycling of flunixin, as was previously reported for phenylbutazone. This study supports that different oral dosing regimens should be used for Asian (1.0 mg/kg SID) and African (1.2 mg/kg SID) elephants, and oral administration techniques used should ensure complete dosage delivery.

A hexafluroisopropanol (HFIP)-alkanol supramolecular solvent (SUPRAS) based magnetic solvent bar (MSB) liquid-phase microextraction (LPME) method was proposed for extraction of non-steroidal anti-inflammatory drugs (NSAIDs, including ketoprofen, naproxen, indomethacin and diclofenac) in human serum. The restricted access HFIP-alkanol SUPRAS was prepared by injecting a mixture of HFIP and alkanol into water. A stainless-steel needle was inserted into a piece of hollow fiber to prepare a magnetic bar. Then the magnetic bar was dipped in SUPRAS to impregnate the wall pores of the hollow fiber, followed by placing it into the serum sample for extraction. Only 4 μL of SUPRAS was consumed per bar. The MSB not only functioned for stirring, but also played the role of extraction and magnetic separation. Under the optimal extraction conditions (seven MSBs, extraction time 33 min and stirring rate 730 rpm), which was obtained by one variable-at-a-time and response surface methodology, the novel MSB-LPME was coupled with high performance liquid chromatography-tandem mass spectrometry to determine NSAIDs in human serum. The method showed a good linear relationship (correlation coefficients ≥ 0.9939). Method limits of detection and method limits of quantitation were in the range of 0.25-0.95 μg L -1 and 0.83-3.16 μg L -1 , respectively. The recoveries for the spiked human serum samples ranged from 86.8% to 125.1% with intra- and inter-day relative standard deviations less than 9.2% and 18.1%, respectively. Moreover, the method did not require a protein precipitation step, and matrix effects of 72.8%-117.7% showed little interference with mass spectrometry detection, which was due to the double cleanup provided by the restricted access property of SUPRAS and the filtration capacity of hollow fiber. The HFIP-alkanol SUPRAS-based MSB-LPME method proved to be simple, highly efficient and environment-friendly for the pretreatment of serum/plasma., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Ethnopharmacological Relevance: Radix Salvia Miltiorrhiza (Danshen) and Radix Pueraria Lobate (Gegen) are officially listed in the Chinese Pharmacopoeia and have long been used together as a Compound Chinese Traditional Medicine (CCTM) for treatment of coronary heart diseases, which are often co-administered with aspirin or warfarin to patients suffering from cardiovascular diseases., Aim of Study: Since significant pharmacokinetic and pharmacodynamic interactions between Danshen-Gegen (DG) formula and aspirin/warfarin have been observed in our previous rat studies, the current study was proposed aiming to further verify such pharmacokinetic and pharmacodynamic interactions in healthy human subjects and explore related mechanisms., Materials and Methods: A 5-day, multiple dose, five-session clinical trial has been carried out (n = 14) with 2-week washout periods between sessions, during which the subjects would receive different combinations of the medications. Plasma samples were collected for pharmacokinetic evaluation, and whole blood samples were collected for pharmacodynamic evaluation. In addition, an in-vitro mechanistic study is conducted to investigate the role of danshensu on the anti-thrombotic and anti-platelet aggregation effects of warfarin and aspirin respectively., Results: Significant pharmacokinetic and pharmacodynamic herb-drug interactions were observed in healthy human subjects. pharmacokinetically, co-administration of DG with aspirin or warfarin could lead to a moderately increased AUC 0→t of aspirin and a decreased AUC 0→t of 7-hydroxyl warfarin respectively. The systemic exposure of danshensu (DSS, the marker component of DG) would be significantly increased after co-administration with warfarin. Pharmacodynamically, a reduction in systemic thromboxane B2 concentration was noticed after administration of DG with aspirin, which could be associated with the increased systemic exposure of aspirin and the synergistic effect of danshensu, aspirin and salicylic acid on cyclooxygenase (COX) inhibition. An offset on the warfarin induced soluble thrombomodulin induction was observed after its co-administration with DG, which could be partially attributed to the COX-2 inhibition effect of danshensu., Conclusion: Our results indicated that co-administration of DG with aspirin/warfarin would lead to significant pharmacokinetic and pharmacodynamic herb-drug interactions in healthy human subjects., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In cynomolgus macaques, plasma levels of sustained-release formulations of meloxicam meet or exceed efficacious concentrations for 48 to 72 h, thereby allowing less animal handling and providing more consistent efficacy than standard formulations of meloxicam. The goal of this study was to compare the pharmacokinetics of a single subcutaneous dose of a sustained-release formulation of meloxicam (Melox-SR) with those of oral (Melox-PO) and standard subcutaneous (Melox-SC) formulations dosed every 24 h for 3 consecutive days. Dogs (5 or 6 adult male Beagles) each received the following 3 treat- ments: first, Melox-SR (10 mg/mL, 0.6 mg/kg SC once), next Melox-SC (0.2 mg/kg SC once, followed by 0.1 mg/kg SC every 24 h), and finally Melox-PO (same dosage as Melox-SC), with a washout period of at least 2 wk between formulations. Blood was collected at 0 (baseline), 1, 4, 8, 12, 24, 48, and 72 h after the initial administration of each formulation for comparison of meloxicam plasma concentrations. Blood was also collected before administration and at 48 h after Melox-SR injection for CBC and chemistry analysis. Plasma concentrations (mean ± 1 SD) of Melox-SR peaked at the 1-h time point (2180 ± 359 ng/ mL), whereas those of Melox-PO (295 ± 55 ng/mL) and Melox-SC (551 ± 112 ng/mL) peaked at the 4-h time point. Melox-SR yielded significantly higher plasma concentrations than Melox-PO and Melox-SC until the 48 and 72-h time points, respec- tively. Melox-SC plasma concentrations were significantly higher than those of Melox-PO at 4, 8, 12, 24, 48 and 72 h. No lesions were noted at the Melox-SR injection sites, and Melox-SR administration was not associated with changes in the CBC and serum chemistry panels. A single 0.6-mg/kg dose of Melox-SR can yield plasma concentrations that exceed 350 ng/mL for at least 72 h in adult male dogs.

Repeated administration of meloxicam to cats is often limited by the potential damage to multiple organ systems. Identifying molecules that predict the adverse effects of meloxicam would help to monitor and individualize its administration, maximizing meloxicam's beneficial effects. The objectives of this study were to (a) determine if the repeated administration of meloxicam to cats alters the plasma metabolome and (b) identify plasma metabolites that may serve to monitor during the administration of meloxicam in cats. Purpose bred young adult cats (n = 12) were treated with meloxicam at 0.3 mg/kg or saline subcutaneously once daily for up to 17 days. An untargeted metabolomics approach was applied to plasma samples collected prior to and at designated time points after meloxicam or saline administration. To refine the discovery of biomarkers, the machine-learning algorithms, partial least squares discriminant analysis (PLS-DA) and random forest (RF), were trained and validated using a separate unrelated group of meloxicam- and saline-treated cats (n = 8). A total of 74 metabolites were included in the statistical analysis. Metabolomic analysis shows that the repeated administration of meloxicam alters multiple substances in plasma, including nonvolatile organic acids, aromatic amino acids, monosaccharides, and inorganic compounds as early as four days following administration of meloxicam. Seventeen plasma molecules were able to distinguish meloxicam-treated from saline-treated cats. The metabolomic changes discovered in this study may help to unveil unknown mechanisms of NSAID-induced side effects. In addition, some metabolites could be valuable for individualizing the administration of meloxicam to cats to mitigate adverse effects., (© 2020 John Wiley & Sons Ltd.)

Background: Robenacoxib (Onsior™) is a non-steroidal anti-inflammatory drug developed for canine and feline use for the control of pain and inflammation. It is available as both tablets and solution for injection. The objective of this study was to evaluate the safety of the interchangeable use of commercially available robenacoxib formulations when administered to cats orally using 6 mg tablets and subcutaneously using a solution for injection containing 20 mg/mL. Thirty-four naïve healthy 4-month old cats were enrolled in this 37-day study and were randomized to four groups (three robenacoxib and one control). One robenacoxib group received the maximum recommended dose (MRD) rate of each formulation, while the other two received two and three times this dose rate. The cats underwent three 10-day treatment cycles comprised of seven days of once daily oral administration followed by three days of subcutaneous administration. The third cycle was followed by an additional seven days of oral treatment. The control group received oral empty gelatin capsules or subcutaneous saline injections. Assessment of safety was based on general health observations, clinical observations, physical, ophthalmic, electrocardiographic and neurological examinations, clinical pathology evaluations, food consumption, body weight, and macroscopic and microscopic examinations. Blood samples were collected for toxicokinetic evaluation., Results: Blood concentrations of robenacoxib confirmed systemic exposure of all treated cats. All cats were in good health through study termination and there were no serious adverse events during the study. There were no changes in body weight, food consumption, ophthalmic, physical or neurological examinations during the study. Treatment-related abnormalities were of low occurrence at all doses and included injection site changes (transient edema with minimal or mild, subacute/chronic inflammation histologically) and prolongation of the QT interval. These findings were consistent with previously observed findings in studies with robenacoxib administered separately orally or subcutaneously in cats. Thus, there were no adverse effects that could be attributed specifically to the interchangeable use of oral and injectable robenacoxib., Conclusions: This 37-day laboratory study supports the safety of interchanging robenacoxib injection at a daily dose of 2 mg/kg with robenacoxib tablets at a daily dose of 1 mg/kg, or vice versa.

Molecularly imprinted polymer (MIP) was synthesized through the coprecipitation method on the graphene oxide anchored pencil lead as a substrate for the first time and applied as an efficient sorbent for pseudo stir bar sorptive extraction of nabumetone. The extracted analyte was determined by a novel spectrophotometric method based on the aggregation of silicate sol-gel stabilized silver nanoparticles in the presence of the analyte. The synthesized polymer was characterized using Fourier transform infrared spectroscopy and field emission scanning electron microscopy. Optimization of important parameters affecting the extraction efficiency was done using central composite design whereas the spectrophotometric method was optimized via one at a time variable. Under the optimal conditions, the calibration curve exhibited linearity in the concentration range of 1.5-20.0 μg L -1 . A limit of detection of 0.20 μg L -1 , an enhancement factor of 393 and relative standard deviations (at 10 μg L -1 , n = 6) of 4.6% and 8.1% for intra- and inter-day analysis were obtained. The developed procedure was successfully utilized for the quantification of traces of nabumetone in tap water and biological samples with the complex matrix including human urine and serum., Competing Interests: Declaration of competing interest The authors declare that is no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The aim of this study was to determine the changes in the pharmacokinetics of meloxicam in goat kids who were castrated following the administration of xylazine. Six goat kids were used for the study. The study was performed in two periods according to a longitudinal study, with a 15-day washout period between periods. In the first period (Control group), 1 mg/kg meloxicam was administered by i.v. route to kids. In the second period (Castration group), the kids were sedated with 0.3 mg/kg xylazine and castration was performed following meloxicam administration. Plasma meloxicam concentration was analyzed using HPLC-UV, and pharmacokinetic parameters were calculated by noncompartmental model. In the control group following the administration of meloxicam, mean elimination half-life (t 1/2 ʎz ), area under the concentration-time curve (AUC 0-∞ ), total body clearance (Cl T ), and volume of distribution at steady-state (V dss ) were 13.50 ± 0.62 hr, 41.10 ± 2.86 hr µg/ml, 24.43 ± 1.75 ml hr -1  kg -1 , and 0.45 ± 0.03 L/kg, respectively. In the castration group, the t 1/2 ʎz of meloxicam prolonged, AUC 0-∞ increased, and Cl T and V dss decreased. In conclusion, the excretion of meloxicam from the body slowed and the t 1/2 ʎz was prolonged in the castrated goat kids following xylazine administration. However, there is a need to determine the pharmacodynamics of meloxicam in castrated goat kids., (© 2020 John Wiley & Sons Ltd.)

Objective: Non-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase (COX) in tissues and used as therapeutic agents in different species. Grapiprant, a member of the piprant class of compounds, antagonizes prostaglandin receptors. It is a highly selective EP4 prostaglandin E 2 receptor inhibitor, thereby limiting the potential for adverse effects caused by wider COX inhibition. The objectives of this study were to determine if the approved canine dose would result in measurable concentrations in horses, and to validate a chromatographic method of analysis for grapiprant in urine and plasma., Study Design: Experimental study., Animals: A total of six healthy, adult mixed-breed mares weighing 502 ± 66 (397-600) kg and aged 14.8 ± 5.3 (6-21) years., Methods: Mares were administered one dose of 2 mg kg -1 grapiprant via nasogastric tube. Blood and urine samples were collected prior to and up to 48 hours after drug administration. Drug concentrations were measured using high-performance liquid chromatography., Results: Grapiprant plasma concentrations ranged from 71 to 149 ng mL -1 with the mean peak concentration (106 ng mL -1 ) occurring at 30 minutes. Concentrations were below the lower limit of quantification (50 ng mL -1 ) in four of six horses at 1 hour and in all six horses by 2 hours after drug administration. Grapiprant urine concentrations ranged from 40 to 4077 ng mL -1 and were still detectable at 48 hours after administration., Conclusions and Clinical Relevance: Currently, there are no published studies looking at the pharmacodynamics of grapiprant in horses. The effective concentration needed to control pain in dogs ranges 114-164 ng mL -1 . Oral administration of grapiprant (2 mg kg -1 ) in horses did not achieve those concentrations. The dose was well tolerated; therefore, studies with larger doses could be conducted., (Copyright © 2020 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Non-steroidal anti-inflammatory drugs are commonly used anti-inflammatory analgesics in clinic. Indomethacin is a kind of NSAIDs and has anti-tumor effect. It can significantly change the growth cycle of cancer cells, inhibit their proliferation. In this paper, the antineoplastic effect of indomethacin and its pharmacokinetic effect were analysed. The result showed that indomethacin had more metabolic distribution in tumor tissues and reached its peak at 4 hours, after that, the clearance rate was slower than that in the blood, with the clearance rate slowest at 6-12 hours. At the same time, the expression of Bcl-2 protein in cancer cells was significantly reduced and weakened, while the expression of Bax protein did not change significantly. Pharmacodynamic studies have proved that IN (Indomethacin) has a strong anti-tumor effect. It can enter into tumor cells through cell membrane and nuclear membrane to have an anti-tumor effect.

Every day, hundreds of millions of people worldwide take nonsteroidal anti-inflammatory drugs (NSAIDs), often in conjunction with multiple other medications. In the bloodstream, NSAIDs are mostly bound to serum albumin (SA). We report the crystal structures of equine serum albumin complexed with four NSAIDs (ibuprofen, ketoprofen, etodolac, and nabumetone) and the active metabolite of nabumetone (6-methoxy-2-naphthylacetic acid, 6-MNA). These compounds bind to seven drug-binding sites on SA. These sites are generally well-conserved between equine and human SAs, but ibuprofen binds to both SAs in two drug-binding sites, only one of which is common. We also compare the binding of ketoprofen by equine SA to binding of it by bovine and leporine SAs. Our comparative analysis of known SA complexes with FDA-approved drugs clearly shows that multiple medications compete for the same binding sites, indicating possibilities for undesirable physiological effects caused by drug-drug displacement or competition with common metabolites. We discuss the consequences of NSAID binding to SA in a broader scientific and medical context, particularly regarding achieving desired therapeutic effects based on an individual's drug regimen.

Purpose: This is a narrative review of the published literature on IV ibuprofen (IVIB) as one of the drugs used in multimodal pain management in inpatients and outpatients pre- and postoperatively and for nonsurgical pain or fever., Methods: The efficacy, concurrent opioid use, pharmacokinetic properties, tolerability, stress response, and postoperative recovery with IVIB, which were investigated in 9 clinical studies, are presented in this narrative review. In total, 1062 adult patients and healthy volunteers were included in these 9 studies; 757 of these subjects received IVIB, and the remaining 305 received either placebo or a comparator medication., Findings: The plasma ibuprofen level with IVIB was twice that with oral ibuprofen, and patients experienced less postoperative pain, decreased opioid use, improved quality of recovery, and reduced postsurgical fatigue and surgical stress response, and used less over-the-counter medication., Implications: Overall, preemptive IVIB should be considered in the analgesic regimen for the management of pre- and postoperative pain, as it has a favorable safety profile, with fewer associated adverse events and serious adverse events, significantly lower levels of perioperative cytokines and catecholamines, and improved peri- and postoperative pain control with a decreased use of opioid medications., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Flunixin meglumine (FM) was investigated for the effectiveness of plasma, oral fluid, and urine concentrations to predict tissue residue depletion profiles in finishing-age swine, along with the potential for untreated pigs to acquire tissue residues following commingled housing with FM-treated pigs. Twenty pigs were housed in groups of three treated and one untreated control. Treated pigs received one 2.2 mg/kg dose of FM intramuscularly. Before treatment and at 1, 3, 6, 12, 24, 36, and 48 h (h) after treatment, plasma samples were taken. At 1, 4, 8, 12 and 16 days (d) post-treatment, necropsy and collection of plasma, urine, oral fluid, muscle, liver, kidney, and injection site samples took place. Analysis of flunixin concentrations using liquid chromatography/tandem mass spectrometry was done. A published physiologically based pharmacokinetic (PBPK) model for flunixin in cattle was extrapolated to swine to simulate the measured data., Results: Plasma concentrations of flunixin were the highest at 1 h post-treatment, ranging from 1534 to 7040 ng/mL, and were less than limit of quantification (LOQ) of 5 ng/mL in all samples on Day 4. Flunixin was detected in the liver and kidney only on Day 1, but was not found 4-16 d post-treatment. Flunixin was either not seen or found less than LOQ in the muscle, with the exception of one sample on Day 16 at a level close to LOQ. Flunixin was found in the urine of untreated pigs after commingled housing with FM-treated pigs. The PBPK model adequately correlated plasma, oral fluid and urine concentrations of flunixin with residue depletion profiles in liver, kidney, and muscle of finishing-age pigs, especially within 24 h after dosing., Conclusions: Results indicate untreated pigs can be exposed to flunixin by shared housing with FM-treated pigs due to environmental contamination. Plasma and urine samples may serve as less invasive and more easily accessible biological matrices to predict tissue residue statuses of flunixin in pigs at earlier time points (≤24 h) by using a PBPK model.

Pharmaceuticals are still considered emerging pollutants affecting both aquatic and terrestrial ecosystems. Scavenging bird species may be exposed to veterinary drugs when they feed on livestock carcasses provided at supplementary feeding stations, as these are often stocked with ailing and/or recently medicated animals. Because those animals may be a source of several different pharmaceutical compounds, analytical methods to evaluate residue levels and exposure potential should enable detection and quantification of as many different compounds as possible, preferably from small sample volumes. Four different extraction methods were tested to conduct HPLC-MS-TOF analysis of some of the most common veterinary drugs used in livestock in Spain. The method deemed most viable was a simple extraction, using methanol and 100 µL of plasma, that allowed quantification of seven antibiotics (tetracycline, oxytetracycline, ciprofloxacin, enrofloxacin, nalidixic acid, trimethoprim, sulfadiazine) and five nonsteroidal anti-inflammatory drugs (NSAIDs) (meloxicam, flunixin, carprofen, tolfenamic acid, phenylbutazone). The method was then applied to analysis of 29 Eurasian griffon vulture ( Gyps fulvus ) nestling samples, wherein enrofloxacin and tolfenamic acid were most commonly detected (69% and 20%, respectively). To our knowledge, this is the first study including NSAIDs in the exposure assessment of different classes of veterinary pharmaceuticals in live avian scavengers.

Scope: The docosahexaenoic acid ester of hydroxy linoleic acid (13-DHAHLA) is a bioactive lipid with anti-inflammatory properties from the family of fatty acid esters of hydroxy fatty acids (FAHFA)., Methods and Results: To explore the biosynthesis of 13-DHAHLA from dietary oils, C57BL/6N mice are gavaged for 8 days with various corn oil/marine oil mixtures containing the same amount of DHA. Plasma levels of omega-3 FAHFAs are influenced by the lipid composition of the mixtures but do not reflect the changes in bioavailability of polyunsaturated fatty acids in plasma. Triacylglycerol-bound DHA and linoleic acid serve as more effective precursors for 13-DHAHLA synthesis than DHA bound in phospholipids or wax esters. Both 13(S)- and 13(R)-DHAHLA inhibit antigen and PGE 2 -induced chemotaxis and degranulation of mast cells to a comparable extent and 13(S)-DHAHLA is identified as the predominant isomer in mouse adipose tissue., Conclusion: Here, the optimal nutritional source of DHA is identified, which supports production of anti-inflammatory FAHFAs, as triacylglycerol-based marine oil and also reveals a possible role of triacylglycerols in the synthesis of FAHFA lipokines., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

ATP-binding cassette (ABCG2) is an efflux transporter that extrudes xenotoxins from cells in liver, intestine, mammary gland, brain and other organs, affecting the pharmacokinetics, brain accumulation and secretion into milk of several compounds, including antitumoral, antimicrobial and anti-inflammatory drugs. The aim of this study was to investigate whether the widely used anti-inflammatory drug meloxicam is an Abcg2 sustrate, and how this transporter affects its systemic distribution. Using polarized ABCG2-transduced cell lines, we found that meloxicam is efficiently transported by murine Abcg2 and human ABCG2. After oral administration of meloxicam, the area under the plasma concentration-time curve in Abcg2 -/- mice was 2-fold higher than in wild type mice (146.06 ± 10.57 µg·h/ml versus 73.80 ± 10.00 µg·h/ml). Differences in meloxicam distribution were reported for several tissues after oral and intravenous administration, with a 20-fold higher concentration in the brain of Abcg2 -/- after oral administration. Meloxicam secretion into milk was also affected by the transporter, with a 2-fold higher milk-to-plasma ratio in wild-type compared with Abcg2 -/- lactating female mice after oral and intravenous administration. We conclude that Abcg2 is an important determinant of the plasma and brain distribution of meloxicam and is clearly involved in its secretion into milk., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Supersaturation drug delivery system (SDDS) based on amorphous solid dispersion (ASD) is a widely used strategy to improve oral absorption of poorly water-soluble drugs by achieving a supersaturated state where drug concentration is significantly higher than drug solubility. However, dissolved drugs tend to recrystallize in gastrointestinal (GI) tract if without effective stabilizing excipients. In this paper, well-recognized polymer (polyvinylpyrrolidone, PVP) and lipid (phosphatidylcholine, PC) excipients are combined as ASD carrier, aiming at investigating the effects on evolution of in vitro supersaturation and in vivo plasma concentration of a model poorly soluble drug indomethacin (IND). Fundamental aspects including polymer/lipid composition ratio, drug loading (DL) degree and administration dose were investigated. The in vitro dissolution profiles of ASDs were assessed by supersaturation degree, duration, maximum achievable drug concentration and dose-normalized efficiency, and correlated with in vivo pharmacokinetic data. Results showed that both in vitro and in vivo concentration-time profiles of IND were significantly varying with abovementioned factors. Solution viscosity, solid-state properties and morphology of ASDs were related to the results. This study revealed fundamental mechanisms of PVP/PC mixture effect on IND supersaturation and oral bioavailability, demonstrating that polymer/lipid mixture could be used as a promising carrier to alter supersaturation profile and oral bioavailability of SDDS products., Competing Interests: Declaration of Competing Interest None, (Copyright © 2020 Elsevier B.V. All rights reserved.)

Berberidis cortex, the dry bark of Berberis L., is used to treat diabetes and contains at least three bioactive components: berberine (BBR), berbamine (BBM) and magnoflorine (MGF). BBR in turn is metabolized into berberrubine (BRB). Although it is possible to quantify each of these components individually in serum, there are currently no methods for simultaneously quantifying all four. Here, we developed a specific and rapid method for simultaneously quantifying BBR, BBM, MGF and BRB in mouse serum using ultra high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Samples were pretreated by protein precipitation, separated using an ACQUITY UPLC® BEH C18 column and detected by a triple quadrupole mass spectrometer with electrospray ionization. The compound [9,10-(OC 2 H 3 ) 2 ]-BBR (d 6 -BBR) was used as internal standard for BBR and BRB, boldine (BOL) for MGF and tetrandrine (TET) for BBM. The m/z transitions for precursor/product ion pairs were 336.1/320.2 for BBR, 305.2/566.3 for BBM, 342.0/297.1 for MGF, 322.1/307.2 for BRB, 342.2/294.3 for d 6 -BBR, 312.2/580.3 for TET and 328.1/265.2 for BOL. We validated our method in terms of selectivity, linearity and lower limit of quantification, accuracy, precision, matrix effect and recovery, dilution integrity and stability. This method showed good linearity from 0.1 to 40 ng/mL for BBR, 8 to 3200 ng/mL for BBM, 5 to 2000 ng/mL for MGF and 0.2 to 80 ng/mL for BRB. The chromatographic run time was 3.9 min, and sample preparation took approximately 15 min per batch. Finally, we used our method to measure BBR, BBM, MGF and BRB in serum from diabetic mice after gavage administration of BBR hydrochloride, BBM hydrochloride, and MGF. This method is precise, accurate and suitable for high-throughput sample analysis., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In the present work, NiFe layered double hydroxide (LDH)/Nylon 6 composite nanofibers were prepared by electrospinning method and used as a new sorbent for the extraction and measurement of non-steroidal anti-inflammatory drugs (naproxen, mefenamic acid, and diclofenac) in whole blood samples. The method is based on micro solid phase extraction (µSPE) by packed sorbent followed by HPLC-UV analysis. Effective parameters on the extraction efficiency were optimized using a central composite design (CCD). In order to characterize the sorbent, Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), field emission scanning electron microscopy (FESEM), energy dispersive X-ray analysis (EDX) and elemental mapping were applied. The method was fully validated based on linearity, limits of detection (LOD) and quantification (LOQ), precision, and recovery. Under the optimal conditions, LOD values were found to be 25 ng mL -1 for naproxen and diclofenac and 15 ng mL -1 for mefenamic acid. A seven-point calibration curve was obtained in the range of 75-2000 ng mL -1 for naproxen and diclofenac and 50-2000 for mefenamic acid. The method showed good linearity with coefficients of determination, r 2 > 0.9962, for the three drugs. In the entire analytical range, the relative standard deviations (RSD%) were less than 8.1%. Finally, the efficiency of the method was investigated for the analysis of the target analytes in human blood samples, and the recoveries were obtained in the range of 90.7-109.8%., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019. Published by Elsevier B.V.)

To the best of our knowledge, limited pharmacokinetic information to establish suitable therapeutic plans is available for Hawksbill turtles. Therefore, the present study aimed to assess the pharmacokinetic features of tolfenamic acid (TA) in Hawksbill turtles, Eretmochelys imbricata, after single intravenous (i.v.) and intramuscular (i.m.) administration at dosage 4 mg/kg body weight (b.w.). The study (parallel design) used 10 Hawksbill turtles randomly divided into equal groups. Blood samples were collected at assigned times up to 144 hr. The concentrations of TA in plasma were quantified by a validated liquid chromatography tandem mass spectrometry (LC-ESI-MS/MS). The concentration of TA in the experimental turtles with respect to time was pharmacokinetically analyzed using a noncompartment model. The C max values of TA were 89.33 ± 6.99 µg/ml following i.m. administration. The elimination half-life values were 38.92 ± 6.31 hr and 41.09 ± 9.32 hr after i.v. and i.m. administration, respectively. The absolute i.m. bioavailability was 94.46%, and the average binding percentage of TA to plasma protein was 31.39%. TA demonstrated a long half-life and high bioavailability following i.m. administration. Therefore, the i.m. administration is recommended for use in clinical practice because it is both easier to perform and provides similar plasma concentrations to the i.v. administration. However, further studies are needed to determine the clinical efficacy of TA for treatment of inflammatory disease after single and multiple dosages., (© 2019 John Wiley & Sons Ltd.)

Previous reports have warned about the influence of spinal cord injury (SCI) on the pharmacokinetics of various drugs. However, the role of SCI in the efficacy and safety of pharmacotherapy remains unknown. Thereby, our aim was to explore the role of SCI on pharmacokinetics and anti-inflammatory effect of naproxen in response to a local inflammatory challenge. Rats received a severe contusive SCI at T9 or sham injury. Pharmacokinetics of a single intravenous dose of naproxen (10 mg kg -1 ) was studied at days 1 and 15 post-surgery. For the anti-inflammatory assessment, carrageenan was subcutaneously injected in forelimb and hindlimb paws at the same post-surgery periods, and naproxen efficacy was evaluated measuring paw swelling. Plasma protein concentrations and body weight changes were also determined. Plasma naproxen levels and pharmacokinetic parameters were unchanged by acute injury, but subacute injury generated alterations in volume of distribution, clearance, and bioavailability, resulting in significantly reduced plasma naproxen concentrations, in the absence of changes in plasma proteins. Assessment of naproxen anti-inflammatory activity during the acute stage of injury could not be determined because of carrageenan failure to elicit swelling. During the subacute stage, naproxen anti-inflammatory effect on forelimbs (above injury) was similar to that observed in sham-injured animals, while it was almost absent in paralyzed hindlimbs. Under conditions of SCI and peripheral inflammation, pharmacokinetics and anti-inflammatory activity of naproxen vary according to post-injury timing and neurological status of the assessed region.

Objective: To describe the efficacy of in-series hemoperfusion and hemodialysis in 2 dogs with carprofen overdose., Case Summary: This report describes the treatment of 2 dogs following accidental carprofen overdoses who underwent a single in-series hemoperfusion and hemodialysis session. Serial serum carprofen concentrations were measured before, during, and after the session. The first patient's session lasted 5 hours, with the largest decrease in serum carprofen concentrations occurring during the first hour of treatment. The carprofen clearance during the following 4 hours of treatment decreased substantially compared to the first hour and was not different from the patient's intrinsic clearance of carprofen after the session was completed. Based on the findings from the first case, the second patient was treated with a 1 hour single hemoperfusion and hemodialysis session. Our results support the hypothesis that carprofen is not effectively removed by conventional hemodialysis and the efficacy of hemoperfusion is short lived due to rapid saturation of the charcoal filter. Once filter saturation occurs, the extracorporeal session is no longer efficacious. Using in-series hemoperfusion and hemodialysis is of benefit to correct the side effects seen with hemoperfusion alone, and hourly charcoal filter replacement may extend the efficacy of treatment in removing carprofen., New or Unique Information Provided: This is the first published report of in-series hemoperfusion and hemodialysis being used to treat carprofen overdose in a dog. In these 2 cases, the intrinsic clearances of the patients were shown to be equivalent to that of standard hemodialysis alone, indicating that hemodialysis does not produce any advantage in carprofen clearance. In this limited report, we suggest that the efficacy of hemoperfusion in removing carprofen is short-lived, and extending the treatment beyond the first hour does not produce any therapeutic benefit. In order to extend the efficacy of hemoperfusion, hourly replacement of the charcoal filter should be considered., (© Veterinary Emergency and Critical Care Society 2020.)

Background: Roux-en-Y gastric bypass (RYGBS), a surgery that creates a smaller stomach pouch and reduces the length of small intestine, is one of the most common medical interventions for the treatment of obesity., Aim: The aim of this study was to determine how RYGBS affects the absorption and metabolism of acetaminophen., Materials and Methods: Ten morbidly obese patients received 1.5 g of liquid acetaminophen (APAP) orally on three separate pharmacokinetic study days (i.e., pre-RYGBS baseline and 3 and 12 months post-RYGBS). Plasma was collected at pre-specified timepoints over 24 hours, and the samples were analyzed using liquid chromatography-mass spectrometry for APAP, APAPglucuronide (APAP-gluc), APAP-sulfate (APAP-sulf), APAP-cysteine (APAP-cys), and APAP-Nacetylcysteine (APAP-nac)., Result: Following RYGBS, peak APAP concentrations at the 3-month and 12-month visits increased by 2.0-fold compared to baseline (p=0.0039 and p=0.0078, respectively) and the median time to peak concentration decreased from 35 to 10 minutes. In contrast, peak concentrations of APAP-gluc, APAP-sulf, APAP-cys, and APAP-nac were unchanged following RYGBS. The apparent oral clearance of APAP and the ratios of metabolite area under the curve (AUC)-to-APAP AUC for all four metabolites decreased at 3 and 12 months post-RYGBS compared to the presurgical baseline. In a simulation of expected steady-state plasma concentrations following multiple dosing of 650 mg APAP every 4 hours, post-RYGBS patients had higher steady-state peak APAP concentrations compared to healthy individuals and obese pre-RYGBS patients, though APAP exposure was unchanged compared to healthy individuals., Conclusion: Following RYGBS, the rate and extent of APAP absorption increased and decreased formation of APAP metabolites was observed, possibly due to downregulation of Phase II and cytochrome P450 2E1 enzymes., (© 2020 Pharmacotherapy Publications, Inc.)

In this study, a green production method was used to obtain magnetic carbon nanodot/graphene oxide hybrid material (Fe 3 O 4 @C-nanodot@GO) for the magnetic solid phase extraction (MSPE) of ibuprofen (IBU) in human plasma prior to HPLC-DAD determination. For the first time in the literature, Fe 3 O 4 @C-nanodot@GO hybrid material was synthesized and used as an adsorbent. C-nanodots were produced from pasteurized cow milk by using a simple and cheap hydrothermal method. After production of the C-nanodots and GO, Fe 3 O 4 @C-nanodot@GO hybrid material was fabricated in green solvent medium by using an one-step hydrothermal method. The method was based on the simple separation, preconcentration and analysis of ibuprofen by using MSPE-HPLC-DAD combination. The concentration changes of ibuprofen in human bloods against time were successfully monitored by using this combined method. For this purpose, blood samples were taken from volunteers at certain intervals after the administration of a certain dose of ibuprofen, and the MSPE method was used to monitor the concentration changes of ibuprofen in the blood samples. Experimental variables affecting the extraction efficiency of IBU such as sample solution pH, amount of adsorbent, extraction time, eluent type and volume were studied and optimized in the details. The characterization studies for the Fe 3 O 4 @C-nanodot@GO were carried out by X-ray diffraction spectrometry (XRD), Fourier transform infrared spectrometry (FT-IR), Raman spectrometry (Raman), energy dispersive x-ray (EDX), vibrating sample magnetometry (VSM) and scanning electron microscopy (SEM) techniques. Under the optimum experimental conditions, the limit of detection (LOD) was 8.0 ng mL -1 and the recoveries at three spiked levels in human plasma were ranged from 91.0% to 95.0% with the relative standard deviation (RSD %) less than 4.0 % (n = 6). The results show that together use of MSPE with HPLC-DAD provides a simple and rapid analysis of ibuprofen in human plasma samples., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In this work, we developed cerium oxide/tin oxide (CeO 2 /SnO 2 ) nanocatalyst with the assistance of urea by a simple sonochemical method and utilized as an efficient electrode material for electrochemical sensing of anti-inflammatory drug 5-aminosalicylic acid (Mesalamine, MES). The CeO 2 /SnO 2 nanoparticles (NPs) were systematically characterized in terms of their crystal structure, morphologies, and physicochemical properties using XRD, Raman, FESEM, HR-TEM, EDX, mapping, and XPS analysis. The characterization results clearly confirmed that the prepared NPs was formed in the phase of CeO2/SnO2 without any other impurities. The electrochemical properties of CeO 2 /SnO 2 NPs were investigated by EIS, CV, and DPV techniques. The CeO 2 /SnO 2 NPs (9.6 μA) modified GCE demonstrated an excellent and improved electrocatalytic activity in terms of higher anodic peak current and lower peak potential when compared to bare GCE (6.7 μA) and CeO 2 NPs/GCE (8.2 μA) for the sensing of MES. The CeO 2 /SnO 2 NPs/GCE shows broader linear response range and lower detection limit of 0.02-1572 μM and 0.006 μM, respectively. Moreover, other potentially interfering compounds such as a similar functional group containing biological substances and inorganic species have no interference effect towards MES sensing. In addition, the practicability of the CeO 2 /SnO 2 NPs/GCE was tested by real sample analysis in commercial MES tablet, human urine, and serum samples with the appreciable recovery results., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: Metamizole is a frequently used antipyretic and analgesic prodrug, yet its pharmacokinetics has not been thoroughly studied in infants and with coadministered medications. Thus, an LC-MS/MS method was developed to quantify the four major metamizole metabolites in human plasma. Methodology: Pre- and postcolumn infusion was installed to enable robust analyte retention and electrospray ionization following deproteinization of plasma samples. Results: The method was linear (R > 0.996), accurate (93.1-106.0%) and precise (≤12.7%). Mean recovery was more than 91.8% and ion suppression less than 13.1% for all analytes. Pharmacokinetic profiles were reproducible after 4 years at -80°C except for the formylated metabolite (-22.2%). Conclusion: The method fulfilled pertinent criteria of validation guidelines and required only little sample volume. The method therefore qualifies for metamizole analyses in children.

Use of drug in lactating animal should be carefully considered due to its possibility of changes in pharmacokinetics as well as drug penetration in milk. The aim of this study was to assess the effect of lactation on pharmacokinetics of meloxicam after IV and IM administrations in goats. A crossover design (2 × 2) was used for each lactating and nonlactating group of goats with a 3-week washout period. Meloxicam (0.5 mg/kg) was administered into the jugular vein and upper gluteal muscle by IV and IM routes, respectively. The plasma and milk drug concentrations were determined by high-performance liquid chromatography with diode array detector, and the pharmacokinetic analysis was carried out by noncompartmental analysis. The pharmacokinetic parameters of meloxicam in lactating and nonlactating goats were not significantly different. The IM bioavailability of meloxicam was relatively lower in lactating (75.3 ± 18.6%) than nonlactating goats (103.8 ± 34.7%); however, the difference was not statistically significant. Moreover, AUC ratio between milk and plasma, which represent drug milk penetration, for both IV and IM administrations was less than 1 (about 0.3). In conclusion, pharmacokinetic parameters of meloxicam are not significantly altered by lactation for either the IV or IM routes of administration and this drug does not require a different dosage regimen for lactating animals., (© 2019 John Wiley & Sons Ltd.)

This study aimed to simultaneously determine mesalazine (5-ASA) and its major metabolite N-Ac-5-ASA in the plasma and to evaluate the impact of different food patterns on the relative bioavailability and pharmacokinetics of a single oral dose of 5-ASA in healthy subjects. In this single-dose, open-label, 3-period, 3-treatment crossover study, the subjects received a single, oral dose of 500-mg enteric-coated mesalazine tablet together with either a low-fat or a high-fat breakfast or under fasting condition (reference). The pharmacokinetic parameters were determined by noncompartmental methods and analyzed with a linear mixed-effect model. The geometric least squares mean ratio for the area under the plasma concentration-time curve from zero to infinity of N-Ac-5-ASA was 1.05 (90% confidence interval [CI], 0.70-1.58) for high-fat/fasted condition and 1.06 (90%CI, 0.82-1.36) for low-fat/fasted condition. The least squares mean ratio of 5-ASA was 0.86 (90%CI, 0.65-1.14) for high-fat/fasted condition and 0.78 (90%CI, 0.60-1.02) for low-fat/fasted condition. All P values were >.05. The mean maximum plasma concentration and the time to reach the maximum plasma concentration of N-Ac-5-ASA were 2084 ng/mL, 8 hours; 2639 ng/mL, 11 hours, and 2409 ng/mL, 9 hours for fasted, high-fat, and low-fat, respectively. The values of 5-ASA were 1950 ng/mL, 7 hours; 2869 ng/mL, 9 hours; and 2837 ng/mL, 8 hours for fasted, high-fat, and low-fat condition. 5-ASA was well tolerated under all 3 conditions. Food delayed the absorption of 5-ASA, especially a high-fat meal. Therefore, enteric-coated mesalazine tablets should be taken before meals to avoid causing patients slow response and any effect of food on its efficacy., (© 2019, The American College of Clinical Pharmacology.)

The purpose of this study was two-fold: I) to determine the pharmacokinetic profile of meloxicam (MLX) in geese after intravenous (IV) and oral (PO) administration and II) to assess tissue residues in muscle, heart, liver, lung, and kidney. Ten clinically normal female Bilgorajska geese were divided into two groups (treated, n = 8; control, n = 2). Group 1 underwent a 3-phase parallel study with a 1-week washout period. In phase I, animals received MLX (0.5 mg/kg) by IV administration; the blood was collected up to 48 hr. In phases II and III geese were treated orally at the same dosage for the collection of blood and tissue samples, respectively. Group 2 served as control. After the extraction procedure, a validated HPLC method with UV detection was used for plasma and organ analysis. The plasma concentrations were quantifiable up to 24 hr after both the administrations. The elimination phase of MLX from plasma was similar in both the administration groups. The clearance was slow (0.00975 L/hr*Kg), the volume of distribution small (0.0487 L/kg), and the IV half-life was 5.06 ± 2.32 hr. The average absolute PO bioavailability was 64.2 ± 24.0%. Residues of MLX were lower than the LOQ (0.1 µg/kg) in any tested tissue and at any collection time. The dosage used in this study achieved the plasma concentration, which provides analgesia in Hispaniolan Amazon parrots for 5 out of 24 hr after PO administration. MLX tissue concentrations were below the LOD of the assay in tissue (0.03 µg/ml). A more sensitive technique might be necessary to determine likely residue concentrations in tissue., (© 2019 John Wiley & Sons Ltd.)

5-aminosalicylic acid (5-ASA) is the most widely used drug for the treatment of ulcerative colitis. The benefits of targeted delivery of 5-ASA to the large intestine are well known, resulting in reduced systemic absorption and increased local concentrations at the disease site. In the present study, a 5-ASA colon delivery system based on the time-dependent strategy, exploiting the relatively consistent small intestinal transit time (SITT), was manufactured and evaluated in vitro as well as in vivo. The system was obtained by successive spray-coating of an immediate-release tablet core with low-viscosity HPMC and Eudragit® L. The enteric film was effective in preventing release during the acidic stage of the in vitro test, while the HPMC coating brought about reproducible lag phases prior to release in phosphate buffer medium. A γ-scintigraphy investigation pointed out that, following administration to fasted and fed volunteers, disintegration of the units never occurred prior to colon arrival. In all cases, a lag time preceded the appearance of the drug and its N-acetyl metabolite in the bloodstream, which was found to correlate with the time of disintegration in a linear mode. The plasma levels of the drug and metabolite as well as their cumulative urinary recovery were relatively low with respect to those reported when 5-ASA is delivered to the small bowel., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In the present work we analyzed the hydrophobicity and hydrophilicity properties of several non-steroidal anti-inflammatory drugs (NSAIDs) by investigating the structural changes of the dynamic hydrogen bond network in order to predict the extraction recovery of NSAIDs from biological fluids set by solid phase extraction (SPE). This work allows investigating the relationship between theoretical descriptors and experimental data using a parameter free method with a strong correlation (Pearson correlation 0.95, p-value 0.0003). The identification and quantification of analytes in human plasma were carried out by high performance liquid chromatography coupled with photodiode array detection (HPLC-PDA) using a Kinetex Evo C 18 (150 x 4.6 mm I.D) protected by a guard column and a mixture of acetonitrile and 10 mM phosphate buffer (pH 2.5) (50:50, v/v) as mobile phase at isocratic conditions. Accuracy (BIAS%) ranged within -2.33% and + 8.05% while precision (RSD%) was less than 5.73%.The mean extraction recovery of the carprofen (IS) was 84.1% and the recovery of NSAIDs from human plasma ranged between 81.9% to 86.6%. LODs and LOQs for all the investigated NSAIDs were 0.003 and 0.01 μg/mL, respectively. The method was validated according to the ICH guide line in the range 0.010-20.0 μg/mL., (Copyright © 2019. Published by Elsevier B.V.)

Purpose: Celecoxib is a selective cyclooxygenase-2 inhibitor widely used in patients with osteoarthritis and rheumatoid arthritis. Recently, nonclinical data on the inhibition of human ether-à-go-go-related gene potassium channels by celecoxib were reported, but there is no compelling evidence for this finding in humans. The aim of this study was to assess the potential effects of celecoxib on cardiac repolarization by conducting a thorough QT study, which was designed in compliance with the related guidelines., Methods: This randomized, open-label, positive- and negative-controlled, crossover clinical study was conducted in healthy male and female subjects. Each subject received, in 1 of 4 randomly assigned sequences, all of the following 3 interventions: celecoxib 400 mg once daily for 6 days; a single dose of moxifloxacin 400 mg, which served as a positive control to assess the assay sensitivity; and water without any drug, which served as a negative control. Serial 12-lead ECG and blood samples for pharmacokinetic analysis were collected periodically over 24 h. Individually RR-corrected QT intervals (QTcI) and Fridericia method-corrected QT intervals (QTcF) were calculated and evaluated., Findings: Twenty-eight subjects were allocated to 1 of the 4 intervention sequences. The largest time-matched mean effects of celecoxib on the QTcI and QTcF were <5 ms, and the upper bounds of the 1-sided 95% CIs of those values did not exceed 10 ms. Moreover, none of the subjects had an absolute QTcI value of >450 ms or a change from baseline in QTcI of >60 ms after multiple administrations of celecoxib. The QTcI did not show a positive correlation with celecoxib concentrations in the range up to ~2700 μg/L. The overall effects of moxifloxacin on the QTcI and QTcF were enough to establish assay sensitivity. No serious adverse events were reported, with a total of 11 AEs reported in 8 subjects., Implications: Celecoxib caused no clinically relevant increase in the QT/QTc interval at the maximum dose level used in current practice settings. ClinicalTrials.gov identifier: NCT03822520., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Pharmacokinetic (PK) studies of oral firocoxib in large animal species have been limited to horses, preruminating calves, and adult camels. The aim of this study was to describe pharmacokinetics and bioavailability of firocoxib in adult goats. Ten healthy adult goats were administered 0.5 mg/kg firocoxib intravenously (i.v.) and per os (p.o.) in a randomized, crossover study. Plasma firocoxib concentrations were measured over a 96-hr period for each treatment using HPLC and mass spectrometry, and PK analysis was performed. The p.o. formulation reached mean peak plasma concentration of 139 ng/ml (range: 87-196 ng/ml) in 0.77 hr (0.25-2.00 hr), and half-life was 21.51 hr (10.21-48.32 hr). Mean bioavailability was 71% (51%-82%), indicative of adequate gastrointestinal absorption of firocoxib. There were no negative effects observed in any animal, and all blood work values remained within or very near reference range at the study's conclusion. Results indicate that oral firocoxib is well-absorbed and rapidly reaches peak plasma concentrations, although the concentration also decreased quickly prior to the terminal phase. The prolonged half-life may suggest tissue accumulation and higher plasma concentrations over time, depending on dosing schedule. Further studies to determine tissue residue depletion, pharmacodynamics, and therapeutic concentrations of firocoxib in goats are necessary., (© 2019 John Wiley & Sons Ltd.)

Purpose: The prodrug metamizole is prescribed intravenously for postoperative pain in children, including off-label use in infants < 1 year. We aimed to assess the pharmacokinetics of the main metabolites of metamizole in children aged 3-72 months., Methods: A single dose of 10 mg/kg metamizole was administered intravenously for postoperative analgesia. Pharmacokinetic samples were drawn at predefined time points. Pharmacokinetics of the main active metabolite 4-methylaminoantipyrine and three other metabolites was characterized by both non-compartmental and population pharmacokinetic analysis. AUC 0-inf of 4-methylaminoantipyrine was calculated by non-compartmental analysis for two age cohorts (3-23 months, 2-6 years) and compared with the 80-125% range of adult dose-adjusted reference exposure (AUC ref ). Population pharmacokinetic analysis investigated age and weight dependency of the pharmacokinetics and optimal dosing strategies to achieve equivalent adult exposure., Results: A total of 25 children aged 5 months-5.8 years (7.8-24.8 kg) with at least one concentration sample were included; 19 children had ≥ 5 predefined samples up to 10 h after metamizole dose administration. AUC 0-inf of 4-methylaminoantipyrine in children 2-6 years was 29.9 mg/L/h (95% CI 23.4-38.2), significantly lower than AUC ref (80-125% range 39.2-61.2 mg/L/h). AUC 0-inf of 4-methylaminoantipyrine in infants < 2 years was 43.6 mg/L/h (95% CI 15.8-119.0), comparable with AUC ref , while infants < 12 months showed increased exposure. Observed variability could be partially explained by covariates weight and age., Conclusions: Age-related changes in pharmacokinetics of 4-methylaminoantipyrine requires reduced weight-based IV dosing in infants < 1 year compared with infants and children up to 6 years (5 versus 10-20 mg/kg) to achieve equivalent adult exposure., Trial Registration: ClinicalTrials.gov identifier: NCT02660177 .