Pharmacokinetics of single-dose rivaroxaban under fed state in obese vs. non-obese subjects: An open-label controlled clinical trial (RIVOBESE-PK).

The evidence of rivaroxaban's pharmacokinetics in obese compared with non-obese populations remains inconclusive. We aimed to compare the pharmacokinetic profile of rivaroxaban between obese and non-obese populations under fed state. Participants who met the study's eligibility criteria were assigned into one of two groups: obese (body mass index ≥35 kg/m2) or non-obese (body mass index 18.5-24.9 kg/m2). A single dose of rivaroxaban 20 mg was orally administered to each participant. Nine blood samples over 48 h, and multiple urine samples over 18 h were collected and analyzed for rivaroxaban concentration using ultra-performance liquid chromatography coupled with tandem mass detector. Pharmacokinetic parameters were determined using WinNonlin software. Thirty-six participants were recruited into the study. No significant changes were observed between obese and non-obese participants in peak plasma concentration, time to reach peak plasma concentration, area under the plasma concentration-time curve over 48 h or to infinity, elimination rate constant, half-life, apparent volume of distribution, apparent clearance, and fraction of drug excreted unchanged in urine over 18 h. Rivaroxaban's exposure was similar between the obese and non-obese subjects, and there were no significant differences in other pharmacokinetic parameters between the two groups. These results suggest that dose adjustment for rivaroxaban is probably unwarranted in the obese population.

Effect of theophylline on serum and milk pharmacokinetics of tylosin following intramuscular administration in lactating goats.

AIM OF THE WORK: The study was conducted to evaluate the influence of theophylline pre-treatment on serum pharmacokinetics and milk elimination of tylosin following single intramuscular (IM) administrations in lactating goats. METHODS AND RESULTS: In a cross-over study, tylosin was injected via intramuscular (IM) at a single dose of 15 mg/kg b.wt. After a one-month washout period goats received theophylline at a daily IM dose of 2 mg/kg b.wt. for seven consecutive days then tylosin was injected IM dose of 15 mg/kg b.wt. two hours after the last theophylline dosing. Blood samples were collected before and at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, and 24 h post-injection. Samples were left to clot and then centrifuged to yield serum. Milk samples were collected before and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h post-injection from each goat by hand milking. Tylosin serum concentrations were determined by high-performance liquid chromatography (HPLC). Tylosin concentrations versus time were analyzed by a noncompartmental method. Tylosin Cmax significantly declined from 1.73 ± 0.10 to 1.01 ± 0.11 µg/ml, and attained Tmax values of 2 and 1 h, respectively in theophylline-pretreated goats. Moreover, theophylline pretreatment significantly shortened the elimination half-life (t1/2el) from 6.94 to 1.98 h, t1/2ka from 0.62 to 0.36 h and the mean residence time (MRT) from 8.02 to 4.31 h, also Vz/F and AUCs decreased from 11.91 to 7.70 L/kg and from 12.64 to 4.57 µg*h/ml, respectively, consequently, theophylline enhanced the clearance (Cl/F) of tylosin from the body. Similarly, tylosin milk concentrations were significantly lower in theophylline-pretreated goats than in goats that received tylosin alone and were detected up to 24 and 72 h in both groups, respectively. Moreover, the t1/2el and AUCs were significantly decreased from 14.68 ± 1.97 to 4.72 ± 0.48 h, and from 181 to 67.20 µg*h/ml, respectively. CONCLUSIONS: The withdrawal period for tylosin in goat milk is at least 72 h. Theophylline pretreatment significantly decreases serum and milk tylosin concentrations to subtherapeutic levels, which could have serious clinical consequences such as failure of therapy. This means that after administering tylosin to goats, milk from these animals should not be consumed for at least 96 h to ensure that the milk is free from residues of the antibiotic.

Moss-produced human complement factor H with modified glycans has an extended half-life and improved biological activity.

Most drugs that target the complement system are designed to inhibit the complement pathway at either the proximal or terminal levels. The use of a natural complement regulator such as factor H (FH) could provide a superior treatment option by restoring the balance of an overactive complement system while preserving its normal physiological functions. Until now, the systemic treatment of complement-associated disorders with FH has been deemed unfeasible, primarily due to high production costs, risks related to FH purified from donors' blood, and the challenging expression of recombinant FH in different host systems. We recently demonstrated that a moss-based expression system can produce high yields of properly folded, fully functional, recombinant FH. However, the half-life of the initial variant (CPV-101) was relatively short. Here we show that the same polypeptide with modified glycosylation (CPV-104) achieves a pharmacokinetic profile comparable to that of native FH derived from human serum. The treatment of FH-deficient mice with CPV-104 significantly improved important efficacy parameters such as the normalization of serum C3 levels and the rapid degradation of C3 deposits in the kidney compared to treatment with CPV-101. Furthermore, CPV-104 showed comparable functionality to serum-derived FH in vitro, as well as similar performance in ex vivo assays involving samples from patients with atypical hemolytic uremic syndrome, C3 glomerulopathy and paroxysomal nocturnal hematuria. CPV-104 - the human FH analog expressed in moss - will therefore allow the treatment of complement-associated human diseases by rebalancing instead of inhibiting the complement cascade.

Pharmacokinetics and residues of florfenicol in Nile tilapia (Oreochromis niloticus) post-oral gavage.

In the study on Oreochromis niloticus, singular oral gavage of florfenicol (FFC) at 15 mg/kg biomass/day was conducted, mimicking approved aquaculture dosing. Samples of plasma, bile, muscle, intestine, skin, liver, kidney, gill, and brain tissues were collected at 0, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, 64, 96, and 128 hours (h) after oral gavage. LC-MS/MS analysis revealed FFC concentrations peaked at 12.15 µg/mL in plasma and 77.92 µg/mL in bile, both at 24 hours. Elimination half-lives were 28.17 h (plasma) and 26.88 h (bile). The residues of FFC ranked muscle>intestine>skin>liver>kidney>gill. In contrast, the residues of florfenicol amine (FFA) ranked kidney>skin>liver>muscle>gill>intestine>brain, particularly notable in tropical summer conditions. The minimum inhibitory concentration of FFC was elucidated against several bacterial pathogens revealing its superior efficacy. Results highlight bile's crucial role in FFC elimination. Further investigation, especially during winter when fish susceptibility to infections rises, is warranted.

Evaluation of dissipation kinetic models to describe trifluralin degradation in soil and assessing the uncertainty of the half-life estimate.

In Australia, trifluralin is one of the commonly used herbicides to manage annual grasses and some broadleaf weeds. However, it may have some ecosystem impacts such as high toxicity to terrestrial and aquatic life, so it is vital to monitor the degradation of trifluralin for a considerable period for environmental safety. For risk assessment purposes, it is necessary to estimate the half-life of trifluralin, which is often evaluated using derived mathematical dissipation models. In the literature, bi-exponential (BEXP) and gamma models were suggested for modelling the dissipation of trifluralin in soil. Both models provide the half-life estimate without discussing the uncertainty of the estimate, which is a shortcoming in the literature. In this paper, we used simulation to illustrate the importance of estimate's uncertainty (standard error) and demonstrated a method to compute the standard error for the half-life estimate mathematically for kinetic dissipation models. Later, we evaluated the performance of the two suggested models using statistical indices. The computation of the half-life and the standard error of the half-life estimate were discussed. This allows us to describe the inference of the half-life parameter and determine whether the half-life estimates are significantly different against the co-variate (moisture) levels. We demonstrated the method to calculate the standard error of the half-life of trifluralin, which allows us to determine the statistical difference between the estimates. In this study, we found that the half-life of trifluralin in soil tends to increase with increasing moisture levels, and the half-life of trifluralin in soil with 100% moisture level is significantly greater than 40% and 70% moisture levels. Our findings suggest that soil moisture levels should be carefully considered before trifluralin application to minimize the non-target environmental damage.

Half-life extension via ABD-fusion leads to higher tumor uptake of an affibody-drug conjugate compared to PAS- and XTENylation.

A critical parameter during the development of protein therapeutics is to endow them with suitable pharmacokinetic and pharmacodynamic properties. Small protein drugs are quickly eliminated by kidney filtration, and in vivo half-life extension is therefore often desired. Here, different half-life extension technologies were studied where PAS polypeptides (PAS300, PAS600), XTEN polypeptides (XTEN288, XTEN576), and an albumin binding domain (ABD) were compared for half-life extension of an anti-human epidermal growth factor receptor 2 (HER2) affibody-drug conjugate. The results showed that extension with the PAS or XTEN polypeptides or the addition of the ABD lowered the affinity for HER2 to some extent but did not negatively affect the cytotoxic potential. The half-lives in mice ranged from 7.3 h for the construct including PAS300 to 11.6 h for the construct including PAS600. The highest absolute tumor uptake was found for the construct including the ABD, which was 60 to 160% higher than the PASylated or XTENylated constructs, even though it did not have the longest half-life (9.0 h). A comparison of the tumor-to-normal-organ ratios showed the best overall performance of the ABD-fused construct. In conclusion, PASylation, XTENylation, and the addition of an ABD are viable strategies for half-life extension of affibody-drug conjugates, with the best performance observed for the construct including the ABD.

Pharmacokinetics and pharmacodynamics of standard nerve agent medical countermeasures in Göttingen Minipigs.

Animal research continues to serve a critical role in the testing and development of medical countermeasures. The Göttingen minipig, developed for laboratory research, may provide many benefits for addressing research questions within chemical defense. Targeted development of the Göttingen minipig model could reduce reliance upon non-human primates, and improve study design, statistical power, and throughput to advance medical countermeasures for regulatory approval and fielding. In this vein, we completed foundational pharmacokinetics and physiological safety studies of intramuscularly administered atropine sulfate, pralidoxime chloride (2-PAM), and diazepam across a broad range of doses (1-6 autoinjector equivalent) using adult male Göttingen minipigs (n=11; n=4-8/study) surgically implanted with vascular access ports and telemetric devices to monitor cardiovascular, respiratory, arterial pressure, and temperature signals. Pharmacokinetic data were orderly and the concentration maximum mirrored available human data at comparably scaled doses clearly for atropine, moderately for 2-PAM, and poorly for diazepam. Time to peak concentration approximated 2, 7, and 20 min for atropine, 2-PAM, and diazepam, respectively, and the elimination half-life of these drugs approximated 2 hr (atropine), 3 hr (2-PAM), and 8 hr (diazepam). Atropine sulfate dose-dependently increased the magnitude and duration of tachycardia and decreased the PR and ST intervals (consistent with findings obtained from other species). Mild hypothermia was observed at the highest diazepam dose. Göttingen minipigs appear to provide a ready and appropriate large animal alternative to non-human primates, and further development and evaluation of novel nerve agent medical countermeasures and treatment strategies in this model are justified.

Lymphatic uptake of the lipidated and non-lipidated GLP-1 agonists liraglutide and exenatide is similar in rats.

Peptides, despite their therapeutic potential, face challenges with undesirable pharmacokinetic (PK) properties and biodistribution, including poor oral absorption and cellular uptake, and short plasma elimination half-lives. Lipidation of peptides is a common strategy to improve their physicochemical and PK properties, making them viable drug candidates. For example, the plasma half-life of peptides has been extended via conjugation to lipids that are proposed to promote binding to serum albumin and thus protect against rapid clearance. Recent work has shown that lipid conjugation to oligodeoxynucleotides, polymers and small molecule drugs results in association not only with albumin, but also with lipoproteins, resulting in half-life prolongation and transport from administration sites via the lymphatics. Enhancing delivery into the lymph increases the efficacy of vaccines and therapeutics with lymphatic targets such as immunotherapies. In this study, the plasma PK, lymphatic uptake, and bioavailability of the glucagon-like peptide-1 (GLP-1) receptor agonist peptides, liraglutide (lipidated) and exenatide (non-lipidated), were investigated following subcutaneous (SC) administration to rats. As expected, liraglutide displayed an apparent prolonged plasma half-life (9.1 versus 1 h), delayed peak plasma concentrations and lower bioavailability (∼10 % versus ∼100 %) compared to exenatide after SC administration. The lymphatic uptake of both peptides was relatively low (<0.5 % of the dose) although lymph to plasma concentration ratios were greater than one for several early timepoints suggesting some direct uptake into lymph. The low lymphatic uptake may be due to the nature of the conjugated lipid (a single-chain C16 palmitic acid in liraglutide) but suggests that other peptides with similar lipid conjugations may also have relatively modest lymphatic uptake. If delivery to the lymph is desired, conjugation to more lipophilic moieties with higher albumin and/or lipoprotein binding efficiencies, such as diacylglycerols, may be appropriate.

Dissipation pattern of tetraniliprole in/on green chilies.

Field and lab experiments explored tetraniliprole dissipation in chili plants. A supervised trial in Devarayapuram village, Coimbatore, assessed the CO2 chili variety (December-March 2018-2019). Using the Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) method and ultra-high-performance liquid chromatography (UHPLC), samples were collected up to 15 d post-application. Initial tetraniliprole deposits on chili fruits, 1-h post-spray, were 0.898 and 1.271 µg g-1 at single and double doses. Over 80% dissipated within 5 d, reaching below detection limits by day 7 and 10 for single and double doses, respectively. Transformation analysis favored first-order kinetics. Tetraniliprole half-life on chili fruit was 1.49 and 1.53 d at recommended and double doses. The safe waiting period was 4.16 and 5.04 d for 60 and 120 g a.i ha-1. This study provides insights into tetraniliprole dynamics in chili plants, crucial for effective pesticide management.

Dissipation and residues of imidacloprid in amaranth under greenhouse and open field cultivations.

Despite the extensive exposure to imidacloprid residues in food plants, there has been little research on imidacloprid residues in amaranth. The dissipation trend and residue behavior of imidacloprid were evaluated to provide guidelines for imidacloprid application on amaranth under open field and greenhouse. The dissipation rate of imidacloprid in amaranth conformed to the first-order kinetic equation, and the half-lives of imidacloprid in amaranth ranged from 0.29 days in open field to 1.29 days in the greenhouse. After 7 and 14 days from the application of imidacloprid (pesticide dosage, 45 or 67.5 g a.i./ha), the amaranth under the open field and greenhouse growth could be consumed safely with average residues of 0.19 and 0.38 mg/kg, respectively. This result demonstrated that the cultivation has the dominant influence on imidacloprid residue, and the residue of imidacloprid in amaranth planting on open field was much lower than that in the greenhouse, indicating a significant difference in the pesticide residues between the two cultivations with a p-value less than 0.05.

Review of valiltramiprosate (ALZ-801) for the treatment of Alzheimer's disease: a novel small molecule with disease modifying potential.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive deterioration, functional impairments, and neuropsychiatric symptoms. Valiltramiprosate is a tramiprosate prodrug being investigated as a novel treatment for AD. AREAS COVERED: The online databases PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms 'ALZ-801' or 'valiltramiprosate.' Alzheon press releases were reviewed for emerging clinical information. Valiltramiprosate is an oral, well-tolerated synthetic valine-conjugate prodrug of tramiprosate. Valiltramiprosate's active metabolite include tramiprosate and 3-sulfopropanoic acid. Proposed mechanism of action is multiligand binding to Aß42 which stabilizes amyloid monomers to prevent peptide aggregation and oligomerization. Pharmacokinetic studies show 52% oral bioavailability, rapid absorption, approximately 40% brain-drug exposure, and near complete renal clearance. Compared to tramiprosate, valiltramiprosate extends plasma tramiprosate half-life and improves interindividual pharmacokinetic variability. Interim analyses from valiltramiprosate's phase II biomarker trial show: (1) significant reductions in plasma p-tau181 and related AD fluid biomarkers; (2) brain structure preservation and reduced hippocampal atrophy by MRI; and (3) improvements on cognitive assessments at multiple timepoints. Its phase III clinical trial in ApoE ε4 homozygotes is near completion. EXPERT OPINION: Valiltramiprosate's clinical trial data show early indications of efficacy with potential disease modifying effect in AD.

In vitro and in vivo stability of a highly efficient long-acting cocaine hydrolase.

It is recognized as a promising therapeutic strategy for cocaine use disorder to develop an efficient enzyme which can rapidly convert cocaine to physiologically inactive metabolites. We have designed and discovered a series of highly efficient cocaine hydrolases, including CocH5-Fc(M6) which is the currently known as the most efficient cocaine hydrolase with both the highest catalytic activity against (-)-cocaine and the longest biological half-life in rats. In the present study, we characterized the time courses of protein appearance, pH, structural integrity, and catalytic activity against cocaine in vitro and in vivo of a CocH5-Fc(M6) bulk drug substance produced in a bioreactor for its in vitro and in vivo stability after long-time storage under various temperatures (- 80, - 20, 4, 25, or 37 °C). Specifically, all the tested properties of the CocH5-Fc(M6) protein did not significantly change after the protein was stored at any of four temperatures including - 80, - 20, 4, and 25 °C for ~ 18 months. In comparison, at 37 °C, the protein was less stable, with a half-life of ~ 82 days for cocaine hydrolysis activity. Additionally, the in vivo studies further confirmed the linear elimination PK profile of CocH5-Fc(M6) with an elimination half-life of ~ 9 days. All the in vitro and in vivo data on the efficacy and stability of CocH5-Fc(M6) have consistently demonstrated that CocH5-Fc(M6) has the desired in vitro and in vivo stability as a promising therapeutic candidate for treatment of cocaine use disorder.

Determine the pharmacokinetics (half-life, volume of distribution and clearance) of AMB-FUBINACA in rats plasma using GC-MS / MS.

BACKGROUND: Several novel synthetic cannabinoids, including methyl 2-(1-(4-fluorobenzyl)-1Hindazole-3-carboxamido)-3-methylbutanoate (AMB-FUBINACA), have recently surfaced on the illicit drug market. To determine the pharmacokinetic properties (half-life, volume of distribution, and clearance) of AMB-FUBINACA in rats plasma, a straightforward, quick, and highly sensitive analytical approach was developed. METHODS: Eighteen Wistar rats were divided into two groups: one control (saline vehicle) and one treatment group (AMB-FUBINACA at 50 mg/kg). Blood samples (400 µL) were withdrawn via catheters immediately before (t = 0) and at 30, 60, 90, 120, and 240 min following injection. Samples were collected into 1 mL tuberculin syringes, then transferred to 1.5 mL plastic tubes containing 5 µL of 1000 IU/mL K3-EDTA (Thomas Scientific). Place the EDTA tubes containing samples in a centrifuge and spin at 1000 g for 10 min at 4 °C. The top layer is the plasma fraction, which is decanted into cryovials and stored at -20 °C until analysis. The gas chromatography tandem mass spectrometry (GC-MS/MS) method was optimized and validated, combined with liquid-liquid extraction, to analyze AMB-FUBINACA in rat plasma. RESULTS: The research method successfully met the validation requirements set by the FDA, demonstrating selectivity and linear calibration curves within a concentration range of 0.5-1000 ng/ml. The correlation coefficient (r2) was determined to be 0.99, indicating a strong linear relationship. The analyte's limit of quantitation (LOQ) was determined to be 1-5 ng/mL. Subsequently, the method was successfully applied to investigate the pharmacokinetics of AMB-FUBINACA in rats' blood samples. Following oral administration, AMB-FUBINACA was rapidly absorbed, with a plasma half-life (t1/2) of 5.91 h, a volume of distribution (Vd) of 203.13 l, and a plasma clearance of 23.81122 L/h. CONCLUSION: These findings contribute to the understanding of AMB-FUBINACA's pharmacokinetics and pharmacodynamics.

The αSynuclein half-life conundrum.

αSynuclein (αSyn) misfolding and aggregation frequently precedes neuronal loss associated with Parkinson's Disease (PD) and other Synucleinopathies. The progressive buildup of pathological αSyn species results from alterations on αSyn gene and protein sequence, increased local concentrations, variations in αSyn interactome and protein network. Therefore, under physiological conditions, it is mandatory to regulate αSyn proteostasis as an equilibrium among synthesis, trafficking, degradation and extracellular release. In this frame, a crucial parameter is protein half-life. It provides indications of the turnover of a specific protein and depends on mRNA synthesis and translation regulation, subcellular localization, function and clearance by the designated degradative pathways. For αSyn, the molecular mechanisms regulating its proteostasis in neurons have been extensively investigated in various cellular models, either using biochemical or imaging approaches. Nevertheless, a converging estimate of αSyn half-life has not emerged yet. Here, we discuss the challenges in studying αSyn proteostasis under physiological and pathological conditions, the advantages and disadvantages of the experimental strategies proposed so far, and the relevance of determining αSyn half-life from a translational perspective.

A crossover study to evaluate the pharmacokinetics and bioequivalence of hydroxychloroquine tablets in healthy Chinese subjects.

AIMS: Hydroxychloroquine (HCQ) has a high variability and a long half-life in the human body. The purpose of this study was to evaluate the bioequivalence of a generic HCQ tablet (test preparation) versus a brand HCQ tablet (reference preparation) under fasting and fed conditions in a crossover design. MATERIALS AND METHODS: This was an open-label, two-period randomized, single-dose, crossover study in 47 healthy Chinese subjects who were sequentially and randomly allocated either to the fed group (high-fat meal; n = 23) or the fasting group (n = 24). Participants in each group were randomized to the two arms to receive either a single 200-mg dose of the test preparation or a 200-mg dose of the reference preparation. The application of the two preparations in each patient was separated by a 28-day washout period, regarded as sufficiently long to avoid significant interference from residual drug in the body. Whole blood samples were collected over 72 hours after drug administration. RESULTS: A total of 23 subjects completed both the fed and the fasting parts of the trial. There were no significant differences in Cmax, AUC0-72h, and T1/2 between the test and reference preparation (p < 0.05). Food had no significant effect on Cmax and T1/2 (p < 0.05), but AUC0-72h values were significantly reduced under fed condition compared to fasting condition (p < 0.05). The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) of Cmax and AUC0-72h were 0.84 - 1.05 and 0.89 - 0.98 in the fed study, and 0.97 - 1.07 and 0.97 - 1.05 in the fasting study, respectively. The carryover effect due to non-zero blood concentrations resulted in higher AUC0-72h values in the second period for both test and reference formulations and had no effect on the statistical results. No serious adverse events were reported. CONCLUSION: The investigation demonstrated that the test and reference preparations are bioequivalent and well tolerated under both fasting and fed conditions in healthy Chinese subjects.

Pharmacokinetics of bromoform in dairy heifers.

AIMS: To determine the pharmacokinetics in dairy heifers after oral and IV administration of bromoform, a potential antimethanogenic agent found in red seaweed, Asparagopsis spp. METHODS: Twenty-four dairy heifers with a mean weight of 319 (SD 36.9) kg were used. The study was conducted in two phases, and each cohort of 12 heifers received an escalating dose of bromoform. In the first phase, 12 heifers successively received doses of 200, 400, 800, and 1600 mg of bromoform orally, separated by a 72-hour washout period. In the second phase, a different cohort of 12 dairy heifers was used. Each heifer received a total of four doses of bromoform separated by a wash-out period of 72 hours. Sequentially the treatments were (for each of the 12 heifers) an oral dose of 50 mg, followed by an IV dose of 50 mg, followed by an oral dose of 100 mg and finally an IV dose of 100 mg.Blood samples were assayed by gas chromatography-mass spectrophotometry for bromoform and dibromomethane to estimate the pharmacokinetic parameters using a non-compartmental analysis. RESULTS: Bromoform was rapidly absorbed as indicated by a short time to the maximum observed concentration of 15 minutes. For the routes of administration and dose ranges investigated, the mean terminal half-life ranged from 0.32 (SE 0.03) hours to 5.73 (SE 1.64) hours when administered orally or IV. With values for the mean area under the curve (AUC) to dose ratio ranging from 0.25 (SE 0.04) to 0.82 (SE 0.19) for oral and 1.39 (SE 0.39) to 4.02 (SE 0.37) for IV administration, bromoform appeared to exhibit non-proportional pharmacokinetic behaviour. The mean absolute bioavailability was 39.13 (SE 10.4)% and 3.36 (SE 0.83)% for 50-mg and 100-mg doses, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Bromoform is rapidly absorbed and exhibits dose dependent elimination kinetics.

In vitro to in vivo extrapolation to derive a metabolism factor for estimating the aggregate exposure to salicylic acid after dermal exposure of its esters.

As part of the safety assessment of salicylate esters in cosmetics, we developed a metabolism factor based on in vitro to in vivo extrapolation (IVIVE) to provide a better estimation of the aggregate internal exposure to the common metabolite, salicylic acid. Optimal incubation conditions using human liver S9 were identified before measuring salicylic acid formation from 31 substances. Four control substances, not defined as salicylic esters but which could be mistaken as such due to their nomenclature, did not form salicylic acid. For the remaining substances, higher in vitro intrinsic clearance (CLint, in vitro) values generally correlated with lower LogP values. A "High-Throughput Pharmacokinetic" (HTPK) model was used to extrapolate CLint, in vitro values to human in vivo clearance and half-lives. The latter were used to calculate the percentage of substance metabolised to salicylic acid in 24 h in vivo following human exposure to the ester, i.e. the "metabolism factor". The IVIVE model correctly reproduced the observed elimination rate of 3 substances using in silico or in vitro input parameters. For other substances, in silico only-based predictions generally resulted in lower metabolism factors than when in vitro values for plasma binding and liver S9 CLint, in vitro were used. Therefore, in vitro data input provides the more conservative metabolism factors compared to those derived using on in silico input. In conclusion, these results indicate that not all substances contribute equally (or at all) to the systemic exposure to salicylic acid. Therefore, we propose a realistic metabolism correction factor by which the potential contribution of salicylate esters to the aggregate consumer exposure to salicylic acid from cosmetic use can be estimated.

Biotransformation and disposition characteristics of HSK7653, a novel long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.

AIM: To investigate the metabolism and disposition characteristics of HSK7653 in healthy male Chinese participants. METHODS: A single oral dose of 80 µCi (25 mg) [14C]HSK7653 capsules was administered to six healthy participants, and blood, plasma, urine and faeces were collected. Quantitative and qualitative analysis was conducted to investigate the pharmacokinetics, blood-to-plasma ratio, mass balance and metabolism of HSK7653. RESULTS: The drug was well absorbed and reached a maximum concentration at 1.25 h. The drug-related components (HSK7653 and its metabolites) were eliminated slowly, with a half-life (t1/2) of 111 h. Unchanged HSK7653 contributed to more than 97% of the total radioactivity in all plasma samples. The blood-to-plasma ratio (0.573-0.845) indicated that HSK7653 did not tend to distribute into blood cells. At 504 h postdose, up to 95.9% of the dose was excreted, including 79.8% in urine and 16.1% in faeces. Most of the radioactivity (75.5% dose) in excreta was unchanged HSK7653. In addition, nine metabolites were detected in urine and faeces. The most abundant metabolite was M6-2, a dioxidation product of HSK7653, which accounted for 4.73% and 2.63% of the dose in urine and faeces, respectively. The main metabolic pathways of HSK7653 in vivo included oxidation, pyrrole ring opening and sulphonamide hydrolysation. CONCLUSION: HSK7653 was well absorbed, slightly metabolized and slowly excreted in humans. The high plasma exposure and long t1/2 of HSK7653 may contribute to its long-lasting efficacy as a long-acting dipeptidyl peptidase-4 inhibitor.