Conjugated bisphenol S metabolites in human serum and whole blood.

Studies have shown that bisphenol S (BPS) is mainly present as its conjugated metabolites in human blood. However, the distribution of conjugated BPS metabolites in different human blood matrices has not been characterized. In this study, paired human serum and whole blood samples (n = 79) were collected from Chinese participants, and were measured for the occurrence of BPS and 4 BPS metabolites. BPS was detectable in 49% of human serum (

The Effect of Daily Methylsulfonylmethane (MSM) Consumption on High-Density Lipoprotein Cholesterol in Healthy Overweight and Obese Adults: A Randomized Controlled Trial.

Interventions to decrease inflammation and improve metabolic function hold promise for the prevention of obesity-related diseases. Methylsulfonylmethane (MSM) is a naturally occurring compound that demonstrates antioxidant and anti-inflammatory effects. Improvements in measures of metabolic health have been observed in mouse models of obesity and diabetes following MSM treatment. However, the effects of MSM on obesity-related diseases in humans have not been investigated. Therefore, the purpose of this investigation was to determine whether MSM supplementation improves cardiometabolic health, and markers of inflammation and oxidative status. A randomized, double-blind, placebo-controlled design was utilized with a total of 22 overweight or obese adults completing the study. Participants received either a placebo (white rice flour) or 3 g MSM daily for 16 weeks. Measurements occurred at baseline and after 4, 8, and 16 weeks. Outcome measures included fasting glucose, insulin, blood lipids, blood pressure, body composition, metabolic rate, and markers of inflammation and oxidative status. The primary finding of this work shows that high-density lipoprotein cholesterol was elevated at 8 and 16 weeks of daily MSM consumption compared to baseline, (p = 0.008, p = 0.013). Our findings indicate that MSM supplementation may improve the cholesterol profile by resulting in higher levels of high-density lipoprotein cholesterol.

Identification of the Bisphenol A (BPA) and the Two Analogues BPS and BPF in Cryptorchidism.

Objective: to explore the association of plasma concentrations of bisphenol A (BPA), bisphenol S (BPS), and bisphenol F (BPF) with unilateral cryptorchidism. In addition, to analyze selected demographic and intraoperative characteristics. Design: Retrospective analysis to determine plasma concentrations of total BPA, BPS and BPF using gas chromatography - mass spectrometry (GC-MS) among prepubertal boys with cryptorchidism and prebupertal male control subjects. During operation, the size, turgor and location of the cryptorchid testes were assessed. Main Outcome Measure: Plasma concentrations of total BPA, BPS and BPF. Results: In children with cryptorchidism, plasma levels of BPA, BPS and BPF were significantly higher compared to the control subjects. For BPA, it was: median value: 9.95 ng/mL vs. 5.54 ng/mL, p<0.05. For BPS, it was: median value: 3.93 ng/mL vs. 1.45 ng/mL, p<0.001. For BPF, it was: median value: 3.56 ng/mL vs. 1.83 ng/mL, p<0.05. In cryptorchid group, BPA was detected in 61.4% samples, BPS in 19.3% and BPF in 19.3%. All the three bisphenols were detected in plasma samples of both the healthy subjects and the study cohort. In the latter group, we found significant higher levels of BPA in boys from urban areas. We found a weak positive correlation between the levels of BPS and BPF and reduced turgor of the testes. Furthermore, results showed weak positive correlations between BPA and BPS levels and the age of the children as well as between BPS and BPF concentrations and the place of residence. Conclusions: Results provide a first characterization of prepubertal boys suffering from cryptorchidism and exposed to different kind of bisphenols. Our study suggests that cryptorchid boys are widely exposed to BPA and, to a lesser extent, also to its alternatives, such as BPS and BPF.

High Antibacterial Activity and Selectivity of the Versatile Polysulfoniums that Combat Drug Resistance.

Sulfonium-ion-containing polymers exhibit significant potential benefits for various applications. An efficient strategy to synthesize a type of antibacterial sulfonium-ion-bearing polypeptoids via a combination of ring-opening polymerization and a post-polymerization functionalization with various functional epoxides is presented. A systematic investigation is further performed in order to explore the influence of the overall hydrophobic/hydrophilic balance on the antimicrobial activity and selectivity of the prepared polysulfoniums. Notably, those chlorepoxypropane-modified polysulfoniums with an optimized amphiphilic balance show higher selectivity toward both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus, than to red blood cells. The polymers also show great efficiency in inhibiting S. aureus biofilm formations, as well as in further eradicating the mature biofilms. Remarkably, negligible antibacterial resistance and cross-resistance to commercial antibiotics is shown in these polymers. The polysulfoniums further show their potent in vivo antimicrobial efficacy in a multidrug-resistant S. aureus infection model that is developed on mouse skin. Similar to the antimicrobial peptides, the polysulfoniums are demonstrated to kill bacteria through membrane disruption. The obtained polypeptoid sulfoniums, with high selectivity and potent antibacterial property, are excellent candidates for antibacterial treatment and open up new possibilities for the preparation of a class of innovative antimicrobials.

Safety and Antitumor Activity of Repeated ASP3026 Administration in Japanese Patients with Solid Tumors: A Phase I Study.

BACKGROUND AND OBJECTIVE: Anaplastic lymphoma kinase gene rearrangements (ALKr) resulting in EML4-ALK proteins occur in a subset of solid tumors and are targeted by ALK inhibitors. Given the development of drug resistance to ALK inhibitors, ALK inhibitors with different kinase selectivity are required. METHODS: This phase I, non-randomized, open-label study evaluated the dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity of ASP3026, a second-generation ALK inhibitor, in Japanese patients with solid tumors. Between 1 June 2011 and 20 January 2014, 29 patients received different daily doses of ASP3026 in the escalation (25 mg, n = 3; 50 mg, n = 3; 75 mg, n = 3; 125 mg, n = 4; 200 mg, n = 3; or 325 mg, n = 7) and expansion (200 mg, n = 6) cohorts. RESULTS: Three patients had DLTs at the 325-mg dose: cataract exacerbation, increased aspartate transaminase and alanine transaminase, and impaired hepatic function (all Grade 3 severity). Thus, the maximum tolerated dose was 200 mg. The treatment-emergent adverse event incidence was 100%; the most common events were nausea (n = 8, 27.6%), decreased appetite (n = 10, 34.5%), and fatigue (n = 9, 31.0%) of mild or moderate severity. Six patients were positive for ALK protein and three had ALKr. Two patients achieved partial responses: one with Ewing sarcoma (75-mg dose group) and one with an ALKr-positive inflammatory myofibroblastic tumor (125-mg dose group). CONCLUSION: ASP3026 at a 200-mg dose may provide therapeutic benefit for patients with solid tumors, with a tolerable safety profile. CLINICAL TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov under the identifier NCT01401504 on July 25, 2011.

Comparative toxicokinetics of bisphenol S in rats and mice following gavage administration.

Bisphenol S (BPS) is a component of polyether sulfone used in a variety of industrial applications and consumer products. We investigated the plasma toxicokinetic (TK) behavior of free (unconjugated parent) and total (parent and conjugated) BPS in rats and mice following a single gavage administration (34, 110, or 340 mg/kg). In male rats, BPS was rapidly absorbed with free BPS maximum concentration (Cmax) reached at ≤2.27 h. Elimination of free BPS in male rats was dose-dependent with estimated half-lives of 5.77-11.9 h. Cmax and area under the concentration versus time curve (AUC) increased with dose although the increase in AUC was more than dose proportional. In male rats, total BPS Cmax was reached ≤2.77 h with both Cmax (≥ 10-fold) and AUC (≥ 15-fold) higher than free BPS demonstrating rapid and extensive conjugation of BPS. In male mice, the increase in Cmax and AUC of free BPS was dose-proportional; Cmax was higher and AUC was lower than in male rats. BPS was cleared more rapidly in male mice (half-life 2.86-4.21 h) compared to male rats (half-life 5.77-11.9 h). Similar to rats, total BPS Cmax (≥ 6-fold) and AUC (≥ 12-fold) were higher than corresponding free BPS. Oral bioavailability of free BPS was low to moderate (rats, ≤ 21%; mice, ≤ 19%). There were some species differences in TK parameters of free and total BPS and limited sex difference in rats and mice. In addition, there were dose-related effects of plasma TK parameters in rats.

Pharmacokinetic interactions of esaxerenone with amlodipine and digoxin in healthy Japanese subjects.

BACKGROUND: To investigate the effects of coadministration of esaxerenone with amlodipine on the pharmacokinetics (PK) of each drug, and of esaxerenone on the PK of digoxin. METHODS: In three open-label, single-sequence, crossover studies, healthy Japanese males received single oral doses of esaxerenone 2.5 mg (Days 1, 15), with amlodipine 10 mg/day (Days 8-18) (Study 1, N = 24); single doses of amlodipine 2.5 mg (Days 1, 21), with esaxerenone 5 mg/day (Days 8-25) (Study 2; N = 20); or digoxin 0.25 mg/day (Days 1-15) with esaxerenone 5 mg/day (Days 11-15) (Study 3; N = 20). PK parameters and safety were assessed. RESULTS: Study 1: esaxerenone peak plasma concentration (Cmax) and time to Cmax were unaltered by amlodipine coadministration, but mean half-life was slightly prolonged from 18.5 to 20.9 h. Geometric least-squares mean (GLSM) ratios for Cmax, area under the plasma concentration-time curve (AUC) from zero to last measurable concentration and from zero to infinity for esaxerenone + amlodipine versus esaxerenone were 0.958, 1.154, and 1.173, respectively. Study 2: corresponding GLSM ratios for amlodipine + esaxerenone versus amlodipine were 1.099, 1.185, and 1.214. Study 3: esaxerenone did not markedly alter digoxin PK. GLSM ratios for Cmax, trough plasma concentration, and AUC during a dosing interval for digoxin versus esaxerenone + digoxin were 1.130, 1.088, and 1.072, respectively. CONCLUSIONS: No drug-drug interactions are expected during combination therapy with esaxerenone and either amlodipine or digoxin, based on a lack of any clinically relevant PK changes. TRIAL REGISTRATION: Studies 1 and 2: JapicCTI-163379 (registered on 20 September 2016); Study 3: JapicCTI-163443 (registered on 24 November 2016).

Metabolomic perturbation precedes glycolytic dysfunction and procreates hyperglycemia in a rat model due to bisphenol S exposure.

Previous studies highlighted bisphenol S (BPS), an industrial chemical responsible for harmful effects comparable to its congener substance bisphenol A (BPA). Accounted for various adversities to biological functions, it could alter the expression of endogenous metabolites in many metabolic processes. The study was aimed to investigate the altered metabolites in hyperglycemic condition triggered by sub-chronic exposure of BPS in serum and urine samples of Wistar rats. Invaded effects of hyperglycemia due to BPS exposure on Wistar rats were investigated by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Metabolomic profiling of serum and urinary metabolites was done by gas chromatography-mass spectrometry (GC-MS) analysis. The metabolomics data were represented by one way ANOVA, principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) along with the mapping of perturbed metabolic pathways. The OGTT and ITT showed increased levels of glucose in treated animals with median and high doses, indicating the manifestation of hyperglycemia. The metabolomic profiling of serum and urine revealed BPS could cause consequential metabolomic perturbation mainly of amino acids, sugars, and organic acids. Furthermore, the extrapolation of Kyoto Encyclopedia of Genes and Genomes (KEGG) based systematic analysis helped to monitor the altered pathways, including amino acids, glycolysis, pyruvate metabolism, etc., which were provoked due to BPS exposure. The overview of the perturbed metabolite profiling in rats promisingly showed early diagnostic markers of hyperglycemic condition triggered due to the BPS exposure. Findings from this study will be helpful towards the exploration of mechanistic insights of several disturbed pathways.

Pharmacokinetic assessment of constituents of Boswellia serrata, pine bark extracts, curcumin in combination including methylsulfonylmethane in healthy volunteers.

OBJECTIVES: Dietary supplements are increasingly used by people with osteoarthritis. Boswellia serrata extract, curcumin, pine bark extract and methylsulfonylmethane have been identified as having the largest effects for symptomatic relief in a systematic review. It is important to understand whether any pharmacokinetic interactions are among the major constituents of these supplements so as to provide information when considering the combination use of these supplements. The aim of this study was to investigate the pharmacokinetics of the constituents alone and in combination. METHODS: This study was a randomized, open-label, single-dose, four-treatment, four-period, crossover study with 1-week washout. The pharmacokinetics of the constituents of these supplements when dosed in combination with methylsulfonylmethane were compared to being administered alone. Plasma samples were obtained over 24 h from 16 healthy participants. Eight major constituents were analysed using a validated ultra-high-performance liquid chromatography-tandem mass spectrometry assay. KEY FINDINGS: The pharmacokinetics of each constituent was characterized, and there were no significant differences in the pharmacokinetic profiles of the constituents when administered as a combination, relative to the constituents when administered alone (P > 0.05). CONCLUSIONS: These data suggest that interactions between the major constituents of this supplement combination are unlikely and therefore could be investigated to manage patients with osteoarthritis without significant concerns for possible pharmacokinetic interactions.

Toxicokinetics of bisphenol S in rats for predicting human bisphenol S clearance from allometric scaling.

Previous data obtained in piglets suggested that despite structural analogy with Bisphenol A (BPA), Bisphenol S (BPS) elimination may proceed more slowly, resulting in a much higher systemic exposure to unconjugated BPS than to BPA. Interspecies allometric scaling was applied to predict the toxicokinetic (TK) parameters of BPS, namely plasma clearance in humans from values obtained in animals, and thus contribute to assessment of the human internal exposure to BPS. Allometric scaling was performed using mean BPS plasma clearance values measured in rats after intravenous administration of 5 mg BPS /kg body weight (BW) and those previously obtained in piglets and sheep using identical IV BPS dosing and analytical procedures. The BPS plasma clearance, evaluated at 0.92 L/kg.h in rats, was proportional to species body weight, enabling the prediction of human BPS plasma clearance by extrapolating to a BW of 70 kg. The estimated BPS plasma clearance in humans was thus 0.92 L/min (0.79 L/kg.h), i.e. about two times lower than the previously estimated BPA clearance (1.79 L/min). By increasing systemic exposure to the active moiety of an environmental estrogenic chemical, this less efficient clearance of BPS in humans, as compared with BPA, might worsen the harmful consequences of replacing BPA by BPS.

Bisphenol A analogs in patients with chronic kidney disease and dialysis therapy.

Bisphenol A (BPA) accumulates in patients with chronic kidney disease (CKD), and hemodialysis filters may contribute to bisphenol burden in patients on hemodialysis (HD). The serum levels of BPA and three BPA analogs, namely, bisphenol B (BPB), bisphenol S (BPS), and bisphenol F (BPF), in 58 patients with CKD, 66 patients on dialysis therapy and 30 healthy control were investigated. The content of four bisphenols (BPs) was also examined in three types of dialysis filters, followed by an in vitro elution experiment to test the release of BPs from the dialysis filters. The serum levels of BPA (r = -0.746, p < 0.05) and BPS (r = -0.433, p < 0.05) in 58 CKD patients and 30 healthy control were correlated with the decrease in estimated glomerular filtration rate. The serum levels of BPs in the HD patients were higher than those in the peritoneal dialysis patients (p < 0.05). In the in vitro study on the BP contents in dialysis filters, BPA was the main form of the BPs in the polysulfone membrane (20.86 ±â€¯1.18 ng/mg) and in the polyamide membrane (18.70 ±â€¯2.88 ng/mg), and a modicum of BPS (0.01 ±â€¯0.01 ng/mg) was detected in the polyethersulfone membrane. The results of the elution experiment were in accordance with the results of BPs content in the dialysis filters. Insufficient renal function may lead to BPs accumulation in patients with CKD, and BPs in dialysis products may cause BPs burden in patients on HD.

Gestational Exposure to Bisphenol A and Bisphenol S Leads to Fetal Skeletal Muscle Hypertrophy Independent of Sex.

Gestational exposure to bisphenol A (BPA) can lead to offspring insulin resistance. However, despite the role that the skeletal muscle plays in glucose homeostasis, it remains unknown whether gestational exposure to BPA, or its analog bisphenol S (BPS), impairs skeletal muscle development. We hypothesized that gestational exposure to BPA or BPS will impair fetal muscle development and lead to muscle-specific insulin resistance. To test this, pregnant sheep (n = 7-8/group) were exposed to BPA or BPS from gestational day (GD) 30 to 100. At GD120, fetal skeletal muscle was harvested to evaluate fiber size, fiber type, and gene and protein expression related to myogenesis, fiber size, fiber type, and inflammation. Fetal primary myoblasts were isolated to evaluate proliferation and differentiation. In fetal skeletal muscle, myofibers were larger in BPA and BPS groups in both females and males. BPA females had higher MYH1 (reflective of type-IIX fast glycolytic fibers), whereas BPS females had higher MYH2 and MYH7, and higher myogenic regulatory factors (Myf5, MyoG, MyoD, and MRF4) mRNA expression. No differences were observed in males. Myoblast proliferation was not altered in gestationally BPA- or BPS-exposed myoblasts, but upon differentiation, area and diameter of myotubes were larger independent of sex. Females had larger myofibers and myotubes than males in all treatment groups. In conclusion, gestational exposure to BPA or BPS does not result in insulin resistance in fetal myoblasts but leads to fetal fiber hypertrophy in skeletal muscle independent of sex and alters fiber type distribution in a sex-specific manner.

A selective and robust UPLC-MS/MS method for the simultaneous quantitative determination of anlotinib, ceritinib and ibrutinib in rat plasma and its application to a pharmacokinetic study.

A selective and robust UPLC-MS/MS method has been firstly developed for simultaneous determination of three anti-tumor tyrosine kinase inhibitors (anlotinib, ANL; ceritinib, CER; ibrutinib, IBR) in rat plasma using cost-effective protein precipitation extraction. LC separation was achieved on Waters XBrige C18 column (50 mm × 2.1 mm, 3.5 µm) under gradient conditions in a run time of 5 min. ESI+ was involved through mass spectrometry. Multiple reaction monitoring transitions were at m/z 408.2 → 339.2 for ANL, 558.2 → 433.2 for CER, 441.0 → 138.0 for IBR, 285.0 → 193.1 for diazepam (internal standard), respectively. The optimized method was validated based on US FDA guideline, EMEA guideline as well as Pharmacopoeia of the People's Republic of China. The assay was linear in the range of 0.1-20 ng mL-1 for ANL, 2-1000 ng mL-1 for CER, 1-500 ng mL-1 for IBR. Intra- and inter-day accuracy and precision for all analytes were ≦13.84% and ≦12.56%, respectively. ANL, CER and IBR were sufficiently stable under most investigated conditions. The optimized method was successfully applied for a pharmacokinetic study after single oral gavage administration of mixture (ANL, CER and IBR) at dose of 6 mg kg-1, 25 mg kg-1 and 10 mg kg-1.

Pharmacokinetics and bioavailability of oral firocoxib in adult, mixed-breed goats.

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.

Nonlinear mixed-effects pharmacokinetic modeling of the novel COX-2 selective inhibitor vitacoxib in dogs.

The objective of this study was to develop a nonlinear mixed-effects model of vitacoxib disposition kinetics in dogs after intravenous (I.V.), oral (P.O.), and subcutaneous (S.C.) dosing. Data were pooled from four consecutive pharmacokinetic studies in which vitacoxib was administered in various dosing regimens to 14 healthy beagle dogs. Plasma concentration versus time data were fitted simultaneously using the stochastic approximation expectation maximization (SAEM) algorithm for nonlinear mixed-effects as implemented in Monolix version 2018R2. Correlations between random effects and significance of covariates on population parameter estimates were evaluated using multiple samples from the posterior distribution of the random effects. A two-compartment mamillary model with first-order elimination and first-order absorption after P.O. and S.C. administration, best described the available pharmacokinetic data. Final parameter estimates indicate that vitacoxib has a low-to-moderate systemic clearance (0.35 L hr-1  kg-1 ) associated with a low global extraction ratio, but a large volume of distribution (6.43 L/kg). The absolute bioavailability after P.O. and S.C. administration was estimated at 10.5% (fasted) and 54.6%, respectively. Food intake was found to increase vitacoxib oral bioavailability by a fivefold, while bodyweight (BW) had a significant impact on systemic clearance, thereby confirming the need for BW adjustment with vitacoxib dosing in dogs.

Comparison of Bisphenol A and Bisphenol S Percutaneous Absorption and Biotransformation.

BACKGROUND: Bisphenol S (BPS) has been widely substituted for bisphenol A (BPA) on thermal papers, but little is known about its skin absorption. OBJECTIVES: We compared the percutaneous absorption and biotransformation of BPS and BPA in vitro and in a controlled human trial. METHODS: Absorption and biotransformation of BPS and BPA were monitored across reconstructed human epidermis at two environmentally relevant doses over 25 h. In the human trial, five male participants handled thermal receipts containing BPS and washed their hands after 2 h. Urine (0-48 h) and serum (0-7.5h) were analyzed for target bisphenols, and one participant repeated the experiment with extended monitoring. BPS data were compared with published data for isotope-labeled BPA ([Formula: see text]) in the same participants. RESULTS: At doses of 1.5 and [Formula: see text] applied to reconstructed human epidermis, the permeability coefficient of BPS (0.009 and [Formula: see text], respectively) was significantly lower than for BPA (0.036 and [Formula: see text], respectively), and metabolism of both bisphenols was negligible. In participants handling thermal receipts, the quantities of BPS and [Formula: see text] on hands was significantly correlated with maximum urinary event flux ([Formula: see text]), but the slope was lower for BPS than BPA ([Formula: see text] and 1.1, respectively). As a proportion of total urinary bisphenol, free BPS [[Formula: see text]: [Formula: see text]] was higher than for free BPA ([Formula: see text]). Postexposure maximum urinary BPS concentrations (0.93 to [Formula: see text]; [Formula: see text]) were in the 93-98th percentile range of BPS in background Canadians ([Formula: see text]; [Formula: see text]). CONCLUSION: Both the in vitro and human studies suggested lower percutaneous absorption of BPS compared with BPA, but a lower biotransformation efficiency of BPS should also be considered in its evaluation as a BPA substitute. https://doi.org/10.1289/EHP5044.

Evaluation of the Safety, Tolerability, Pharmacokinetics, and Food Effect of Danirixin Hydrobromide Tablets in Japanese Healthy Elderly Participants.

Danirixin is a selective and reversible CXC chemokine receptor 2 antagonist that may be useful for the treatment of respiratory diseases such as chronic obstructive pulmonary disease. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of danirixin after administration of single oral doses of 10, 50, and 100 mg danirixin hydrobromide (HBr) tablets in the fed state (high-fat meal) (part 1) and to evaluate the food effect (low-fat meal) on the pharmacokinetics of danirixin after administration of a single oral dose of 50 mg danirixin HBr tablets (part 2). A total of 34 Japanese healthy elderly male participants were enrolled; 18 participants were included in part 1, and 16 in part 2. The systemic exposure to danirixin (maximum blood concentration [Cmax ] and area under the concentration-time curve [AUC0-t ]) increased in an approximately dose-proportional manner. The exposure to danirixin was lower in the fed state (low-fat meal) than in the fasted state (a 56% and 35% decrease in Cmax and AUC0-t , respectively). This first study of danirixin in Japanese healthy elderly participants showed a favorable safety profile with no drug-related adverse events and no clinically significant concerns in clinical laboratory values, vital signs, ocular examination, or electrocardiograms.

Pharmacokinetics of vitacoxib in rabbits after intravenous and oral administration.

This study describes the pharmacokinetics of vitacoxib in healthy rabbits following administration of 10 mg/kg intravenous (i.v.) and 10 mg/kg oral. Twelve New Zealand white rabbits were randomly allocated to two equally sized treatment groups. Blood samples were collected at predetermined times from 0 to 36 hr after treatment. Plasma drug concentrations were determined using UPLC-MS/MS. Pharmacokinetic analysis was completed using noncompartmental methods via WinNonlin™ 6.4 software. The mean concentration area under curve (AUClast ) for vitacoxib was determined to be 11.0 ± 4.37 µg hr/ml for i.v. administration and 2.82 ± 0.98 µg hr/ml for oral administration. The elimination half-life (T1/2λz ) was 6.30 ± 2.44 and 6.30 ± 1.19 hr for the i.v. and oral route, respectively. The Cmax (maximum plasma concentration) and Tmax (time to reach the observed maximum (peak) concentration at steady-state) following oral application were 189 ± 83.1 ng/ml and 6.58 ± 3.41 hr, respectively. Mean residence time (MRTlast ) following i.v. injection was 6.91 ± 3.22 and 11.7 ± 2.12 hr after oral administration. The mean bioavailability of oral administration was calculated to be 25.6%. No adverse effects were observed in any rabbit. Further studies characterizing the pharmacodynamics of vitacoxib are required to develop a formulation of vitacoxib for rabbits.

Pharmacokinetics of the novel COX-2 selective inhibitor vitacoxib in cats: The effects of feeding and dose.

The purpose of this study was to determine the pharmacokinetics and dose-scaling model of vitacoxib in either fed or fasted cats following either oral or intravenous administration. The concentration of the drug was quantified by UPLC-MS/MS on plasma samples. Relevant parameters were described using noncompartmental analysis (WinNonlin 6.4 software). Vitacoxib is relatively slowly absorbed and eliminated after oral administration (2 mg/kg body weight), with a Tmax of approximately 4.7 hr. The feeding state of the cat was a statistically significant covariate for both area under the concentration versus time curve (AUC) and mean absorption time (MATfed ). The absolute bioavailability (F) of vitacoxib (2 mg/kg body weight) after oral administration (fed) was 72.5%, which is higher than that in fasted cats (F = 50.6%). Following intravenous administration (2 mg/kg body weight), Vd (ml/kg) was 1,264.34 ± 343.63 ml/kg and Cl (ml kg-1  hr-1 ) was 95.22 ± 23.53 ml kg-1  hr-1 . Plasma concentrations scaled linearly with dose, with Cmax (ng/ml) of 352.30 ± 63.42, 750.26 ± 435.54, and 936.97 ± 231.27 ng/ml after doses of 1, 2, and 4 mg/kg body weight, respectively. No significant undesirable behavioral effects were noted throughout the duration of the study.

Pharmacokinetics of TAK-875 and its toxic metabolite TAK-875- acylglucuronide in rat plasma by liquid chromatography tandem mass spectrometry.

TAK-875 is a selective partial agonist of human GPR40 receptor, which was unexpectedly terminated at phase III clinical trials owing to its severe hepatotoxicity. The purpose of this study was to investigate the pharmacokinetics of TAK-875 and its toxic metabolite TAK-875-acylglucuronide in rat plasma by liquid chromatography tandem mass spectrometry (LC-MS/MS). Plasma samples were extracted with ethyl acetate and chromatographic separations were achieved on a C18 column with water and acetonitrile containing 0.05% ammonium hydroxide as mobile phase. The sample was detected in selected reaction monitoring mode with precursor-to-product ion transitions being m/z 523.2 → 148.1, m/z 699.3 → 113.1 and m/z 425.2 → 113.1 for TAK-875, TAK-875-acylglucuronide and IS, respectively. The assay showed good linearity over the tested concentration ranges (r > 0.9993), with the LLOQ being 0.5 ng/mL for both analytes. The extraction recovery was >78.45% and no obvious matrix effect was detected. The highly sensitive LC-MS/MS method has been further applied for the pharmacokinetic study of TAK-875 and its toxic metabolite TAK-875-acylglucuronide in rat plasma. Pharmacokinetics results revealed that oral bioavailability of TAK-875 was 86.85%. The in vivo exposures of TAK-875-acylglucuronide in terms of AUC0-t were 17.54 and 22.29% of that of TAK-875 after intravenous and oral administration, respectively.