Knowledge of inter-strain and inter-gender differences in drug metabolism studies is important for animal selection in pharmacokinetic and toxicological studies. The effects of rat strain and gender in in vitro metabolism were investigated in Sprague Dawley (SD) and Wister Han (WH) rats based on the hepatocyte metabolic profiles of 14 small molecule drugs. Similarities were found between the hepatocyte

Partial or complete deficiency in the dihydropyrimidine dehydrogenase (DPD) has been observed in 3%–5% and 0.1% of the general population, respectively. It causes severe toxicity in the context of 5-fluorouracil (5-FU) therapy. However, the current tests for determination of DPD deficiency have limitations in routine clinical usage. Therefore, an in vitro approach for simulating 5-FU degradation was

The metabolism of bifenthrin (BIF), β-cyfluthrin (CYFL), λ-cyhalothrin (CYHA), cyphenothrin (CYPH) and esfenvalerate (ESF) was studied in liver microsomes, liver cytosol and plasma from male Sprague-Dawley rats aged 90, 21 and 15 days and from adult humans. Pyrethroid metabolism was also studied with some human expressed cytochrome P450 (CYP) and carboxylesterase (CES) enzymes. All five pyrethroids

We closely characterized 7-Dimethylamino-4-trifluromethylcoumarin (Coumarin 152, C152), a substrate metabolized by multiple P450 species, to establish a new fluorogenic probe for the studies of functional integration in the cytochrome P450 ensemble, Scanning fluorescence spectroscopy and LC/MS-MS were used to characterize the products of N-demethylation of C152 and optimize their fluorometric detection

MGV354 was being developed as a novel ocular therapy for lowering of intraocular pressure, a key modifiable risk factor for glaucoma. MGV354 is an activator of soluble guanylate cyclase, an enzyme known to be involved in the regulation of IOP. MGV354 has been shown to robustly lower IOP over 24 hours after a single topical ocular drop in rabbit and monkey pharmacology models. However, MGV354 failed

Fenarimol (FNL), an organic chlorinated fungicide, is widely used in agriculture for protection from fungal spores and fungi. Despite being an endocrine disruptor, no toxicokinetic data is reported for this fungicide. In the present work, we determined the plasma protein binding, metabolic pathways and toxicokinetics of FNL in rats. In vitro binding of FNL to rat and human plasma proteins was ∼90%

Hydrocoptisonine is a new compound that has been isolated from the rhizomes of Coptis chinensis, which belongs to the Ranunculaceae family of Chinese medicines. Although studies on C. chinensis have been reported, the metabolic pathway of hydrocoptisonine in human liver microsomes (HLMs) remains unelucidated. We identified 13 metabolites in HLMs, including six Phase I metabolites and seven glucuronide

Oral antidyslipidaemic drug pemafibrate is cleared from human plasma via hepatic uptake by organic anion transporting polypeptide (OATP) 1B1 and oxidation by cytochromes P450 (P450) 2C8, 2C9, and 3A4. The pharmacokinetic profiles of pemafibrate with virtual administrations of P450 inhibitors and/or disease interactions were generated using a physiologically based pharmacokinetic (PBPK) model previously

The study aims to establish the plasma pharmacokinetic parameters of levofloxacin in mixed-breed dogs, at a single dose of 5 mg/kg, intravenously, orally only and orally with sucralfate pre-treatment (1g per animal), to evaluate its influence on antimicrobial absorption. Concentrations of levofloxacin in plasma were determined using high performance liquid chromatography (HPLC) with fluorescence detection

Quercetin (QCN) is commonly used in high doses as dietary supplement for weight loss. Psychotic patients are at greater risk of developing obesity than the general population. The present study was designed to understand the impact of QCN on the exposure of quetiapine (QTE), an anti-psychotic drug with narrow therapeutic index and brain penetrating capability. The content of QTE in rat plasma was analyzed

Although CYP2C19 is minor human liver enzyme, it is responsible for the metabolism of many clinically important drugs. In the present work, CYP2C19 wild type and its SNP mutants (R132Q and W120R) were prepared using over-expression system in E. coli, purified by column chromatography and their biological activities were compared. The enzyme activity toward certain drugs (amitriptyline, imipramine,

Challenges and opportunities within peptide ADME (absorption, distribution, metabolism and elimination) were presented and discussed at the 2nd workshop of the Peptide ADME Discussion Group in Cambridge, UK (17th of September 2019). This article summarises the presentations and discussions from this workshop. The following topics were covered: Peptide drug-drug interactions (DDIs) Regulatory perspectives

Primates exhibit a high degree of among-species dietary diversity, which likely exposes them to varying levels of xenobiotic compounds. Here, we examined the evolution of primate CYP1-3 gene families, and we classified the 15 CYP1-3 gene subfamilies as either xenobiotic-metabolizing (XM) or endogenous-metabolizing (EM) based on sources in the P450 literature. We predicted that XM P450s would show (1)

To date, relatively little is known about the interactions of pharmaceutical excipients with hepatic and renal drug uptake transporters. The present study was designed to systematically evaluate the effects of sixteen commonly consumed excipients on human organic cation transporter 1 and 2 (hOCT1 and hOCT2), human organic anion transporter 1 and 3 (hOAT1 and hOAT3) and human organic anion transporting

TQ-A3326 has been developed as a new drug by modifying the structure of daclatasvir with deuterium. The pharmacokinetics (PK) of TQ-A3326 in human remains unclear. The aim of the present study was to establish a LC-MS/MS method to investigate preliminarily the PK characteristics of TQ-A3326 and its major metabolites in healthy Chinese volunteers. All volunteers were administrated TQ-A3326 (60 mg).

Triclocarban is a residue-producing antibacterial agent used in a variety of consumer products. These studies investigated the disposition and metabolism of [14C]triclocarban. In male rats following a single gavage administration of 50, 150, and 500 mg/kg, excretion was primarily via feces (feces, 85-86%; urine, 3-6%) with no apparent dose-related effect. In male rats, 29% of the administered dose

The specialty amine catalyst 2,2′-dimorpholinodiethyl ether (DMDEE) is a high-production volume chemical used in the production of flexible foam, high-resilient molded foam, and in coatings and adhesives. The disposition and metabolism of [14C]DMDEE (20 or 200 mg/kg) were determined in male ane female rats and mice after oral and intravenous administration and dermal application. In male and female

The use of IBH-5 decreased the kdeg values and increased the half-life of the compounds PNZ, TCP, Cpd I and Cpd II with kdeg values of 1.10 × 10−4 s− 1 (t1/2 = 115 min), 4 × 10−5 s−1 (t1/2 = 289 min), 4 × 10−5 s−1 (t1/2 = 289 min), and 3 × 10−5  s−1 (t1/2 = 385 min) respectively, compared to kdeg values of 1.25 × 10−2  s−1 (t1/2 = 0.9 min), 1.1 × 10−4 s−1 (t1/2 = 105 min), 1.0 × 10−3 s−1 (t1/2 = 11

OATP1B1 is an important drug transporter with a complex regulatory mechanism. In this study, we wanted to investigate how LncRNA HOTAIR regulates the expression of OATP1B1 through its action on miR-206/miR-613 in HepG2 cells. The expression level of LncRNA HOTAIR, miR-206/miR-613, and OATP1B1 mRNA was detected by RT-qPCR, and the OATP1B1 protein level was detected by Western blot. The competitive endogenous

We aimed to establish a population pharmacokinetic (PK) model of tacrolimus and identify clinical covariates, especially the genetic polymorphisms of CYP3A5, ABCB1 and POR*28 that affected the PK to prevent fluctuation in the trough concentration of tacrolimus during the early period after renal transplantation. Tacrolimus trough concentration, clinical data and CYP3A5/ABCB1/POR28 genotypes were retrospectively

The objective of this study was to compare the pharmacokinetics of vancomycin hydrochloride administered into rabbits through different routes and explore the feasibility of peptide drugs entering the systemic circulation through ocular administration. A convenient, accurate, and rapid liquid chromatography-trandem mass spectrometric (LC-MS/MS) method was established and used for the determination

Diclofenac is an extensively used nonsteroidal anti-inflammatory drug, but gastrointestinal liabilities and cardiovascular complications take the shine away from such a widely prescribed drug. On the other hand, rutin, a dietary bioflavonoid, has quite a few pharmacological attributes to improve the efficacy and reduce the dose-related toxicities of diclofenac through the intended food/herb-drug interaction

Pesticides are now recognised to interact with drug transporters, but only few data are available on this issue for carbamate pesticides, a widely-used class of agrochemicals, to which humans are highly exposed. The present study was therefore designed to determine whether four representative carbamate pesticides, i.e., the insecticides aminocarb and carbofuran, the herbicide chlorpropham and the fungicide

We previously reported a prediction method for human pharmacokinetics (PK) using single species allometric scaling (SSS) and the complex Dedrick plot in chimeric mice with humanized liver to predict the total clearance (CLt), distribution volumes in steady state (Vdss) and plasma concentration-time profiles of several drugs metabolized by cytochrome P450 (P450) and non-P450 enzymes. In the present

First dose prediction is challenging in neonates. Our objective in this proof-of-concept study was to perform a pharmacokinetic (PK) bridging study from juvenile mice to neonates for drugs metabolized by CYP3A.We selected midazolam and clindamycin as model drugs. We developed juvenile mice population PK models using NONMEM. The PK parameters of these two drugs in juvenile mice were used to bridge PK

Recently, alternatives to animal testing have been used to evaluate skin sensitisers in cosmetic products. However, testing is still complicated and expensive. To develop a simpler, cost-effective and more accurate evaluation method for the skin sensitising chemicals, we employed cell-based and RT-PCR-based assay.Representative sensitiser specific gene expression in THP-1 cells was analysed by microarray

Viloxazine is currently being developed as a treatment for attention deficit/hyperactivity disorder (ADHD). The aim of these studies is to update the understanding of the rat and human metabolism and the in vitro drug-drug interaction profile of viloxazine to a degree where it meets current regulatory standards for such investigations.In vivo ADME studies demonstrated that in humans 5-hydroxylation

Hepatocellular carcinoma (HCC) is a malignancy of liver cells. Recent studies have shown that HCC patients often have changes in the activities of transporters and metabolic enzymes, which can considerably affect drug pharmacokinetics and lead to drug toxicity. Doxorubicin (DOX) has been frequently administered in chemotherapy for HCC, but to our knowledge, the effects of HCC on the pharmacokinetics

Horses are exposed to various kinds of medication, however, there are limited determinations of plasma clearance (CLp) for the drugs used due to the high cost of equine in vivo studies.Many of the CLp values generated come from the equine sports industry for determining drug plasma screening limits in the control of medications at the time of competition.The kinetics of omeprazole metabolism were investigated

The compound 20(S),25-epoxydammarane-3β,12β,24α-triol (24-hydroxy-panaxadiol or 24-OH-PD), isolated from the red Panax ginseng CA Meyer possesses anticancer activity. Our aim was to study the pharmacokinetic characteristics of 24-OH-PD, which is essential for pre-clinical research during the development of new drugs.In this study, a simple and sensitive ultra-performance liquid chromatography-mass

Peimine is a major component of Fritillaria ussuriensis, which is a widely used herb in pediatric. It is very common in Chinese traditional medicine to combine with two or more herbs in the clinic. To investigate the effect of peimine on the activity of cytochrome P450 enzymes (CYP450) is necessary for the clinical application of peimine. The effects of peimine on eight human liver CYP isoforms (i

Herbs are often administered in combination with therapeutic drugs, raising the possibility for herb–drug interactions (HDIs). Furoquinoline alkaloids are found in Rutaceae plants, which are structurally similar and have many medicinal properties. This study aims to investigate the inhibition of four furoquinoline alkaloids on the activity of UDP-glucuronosyltransferases (UGTs). The recombinant UGTs-catalyzed

Liver enzymes and transporters play an essential role in xenobiotic metabolism, distribution and elimination. Pre-clinical safety assessment relies on studies on animal models, including the (mini)pig. The pig shares many anatomical and physiological characteristics with humans, and there is currently a gap in information about porcine metabolism and disposition pathways and their similarities and

2′-, 3′-, and 4′-Methoxyflavones (MeFs) were incubated with nine forms of recombinant human cytochrome P450 (P450 or CYP) enzymes in the presence of an NADPH-generating system and the products formed were analyzed with LC-MS/MS methods. CYP1B1.1 and 1B1.3 were highly active in demethylating 4′MeF to form 4′-hydroxyflavone (rate of 5.0 nmol/min/nmol P450) and further to 3′,4′-dihydroxyflavone (rates

Aspirin (acetyl salicylic acid) is widely used co-medication in patients with cardiovascular and cerebrovascular diseases. Given the prevalence of acetyl salicylic acid’s use as a co-medication and conflicting reports in the literature on it being a substrate of P-glycoprotein (P-gp). There is a potential risk for its interaction with compounds with P-gp liability, therefore, we have conducted a detailed

Ethanol, as a small-molecule organic compound exhibiting both hydrophilic and lipophilic properties, quickly pass through the biological barriers. Over 95% of absorbed ethanol undergoes biotransformation, the remaining amount is excreted unchanged, mainly with urine and exhaled air. The main route of ethyl alcohol metabolism is its oxidation to acetaldehyde, which is converted into acetic acid with

WCK 771 (INN: levonadifloxacin) is a novel antibacterial agent belonging to benzoquinolizine subclass of fluoroquinolones which is under clinical development as a parenteral formulation and its prodrug WCK 2349 (INN: alalevonadifloxacin) as an oral option. Both the drugs have been approved recently in India based on phase III trial completed for ABSSSI. In vitro CYP inhibition potential of levonadifloxacin

Trastuzumab deruxtecan (T-DXd, DS-8201a) is an antibody-drug conjugate (ADC), comprising an anti-HER2 antibody (Ab) at a drug-to-Ab ratio of 7–8 with the topoisomerase I inhibitor DXd. In this study, we investigated the pharmacokinetics (PK), biodistribution, catabolism, and excretion profiles of T-DXd in HER2-positive tumour-bearing mice. Following intravenous (iv) administration of T-DXd, the PK

(2020). Referee acknowledgements. Xenobiotica: Vol. 50, No. 6, pp. 741-745.

Elucidating the mechanisms for circadian expression of drug-metabolizing enzymes is essential for a better understanding of dosing time-dependent drug metabolism and pharmacokinetics. CYP2B6 (Cyp2b10 in mice) is an important enzyme responsible for metabolism and detoxification of approximately 10% of drugs. Here, we aimed to investigate a potential role of nuclear receptor co-repressor RIP140 in circadian

(2020). Expression of Concern. Xenobiotica. Ahead of Print.

This study aimed to evaluate the pharmacokinetics and pharmacodynamics of oral levetiracetam therapy in drug refractory adult epileptic outpatients, as well as factors affecting them. Concentration–time data were collected at steady state, while seizure recurrence was monitored for 13 months. Non-linear mixed effects modeling was applied, and covariates assessed included weight, height, age, daily

Plasma pharmacokinetics (PK) and tissue disposition of enrofloxacin (EFX) was studied in rainbow trout (Oncorhynchus mykiss) after a single oral administration of 10 mg/kg, and by immersion baths of 20 ppm during 2.5 h and 100 ppm during 0.5 h, at water temperature of 16.3 ± 0.3 °C. Concentrations of EFX in plasma and tissues (skin, muscle, liver, kidney and gut) were determined using high performance

Osthol, a pharmacologically active ingredient in various traditional Chinese medicines, is predominantly metabolized by CYP2C9. It may be co-administered with other drugs which are metabolized by CYP2C9 in clinical medicine. However, CYP2C9*1/*2/*3 genotype on the pharmacokinetics of osthole and its metabolic diversity between rat and human are unclear. In this study, we investigated the effects of

Abstract Corylifol A (CA), a phenolic compound from Psoralea corylifolia, possessed several biological properties but poor bioavailability. Here we aimed to investigate the roles of cytochromes P450s (CYPs), UDP-glucuronosyltransferases (UGTs) and efflux transporters in metabolism and disposition of CA. Metabolism of CA was evaluated in HLM, expressed CYPs and UGTs. Chemical inhibitors and shRNA-mediated

We assessed the contribution of CYP2C19 and CYP3A4 metabolic activity to the ADP-induced platelet aggregation 1h and 24h after a loading dose of 60 mg prasugrel or 180 mg ticagrelor in patients with ST-elevation myocardial infarction (STEMI). Further, we assessed the contribution of CYP2C19 polymorphisms and medication to the CYP enzymatic activity. Patients with STEMI were randomly assigned to the

The current research explored the effect of hepatic and renal dysfunctions on the pharmacokinetics of thymoquinone (TQ) in a rat model.An acute kidney injury was induced using gentamicin and a liver damage was elicited using a single dose of d-galactosamine. For the pharmacokinetic studies, TQ was administered as IV injection or and PO route to rats.The concentrations of TQ and pharmacokinetic parameters

Coumarins have aroused high interests due to their diverse bioactivities. Understanding of its metabolism contributes to determine the druggability of coumarin in vivo. A sensitive and efficient strategy based on ultra-performance liquid chromatography-mass spectrometer (UPLC-MS) analysis combined with various data-processing techniques including metabolomics and multiple mass defect filter (MMDF)

An expanded view of the substrate landscape of organic anion transporting polypeptide (OATP) 2B1 was pursued with the goal of understanding if the identification of novel in vitro substrates could shed additional light on the impact of OATP2B1 on intestinal absorption and brain penetration. To examine this hypothesis, a series of experiments measured the cellular accumulation of a diverse array of

Apatinib, a small molecule anti-angiogenic tyrosine kinase inhibitor is used extensively to treat advanced gastric cancer and simvastatin (SV) is often co-prescribed to treat cardiovascular disease in cancer patients. As both apatinib and SV are metabolized primarily by cytochrome P450 variant CYP3A4, they are likely to interact. Therefore, the potential effect of SV co-administration on pharmacokinetics

1. The absorption, distribution, metabolism, elimination, and drug-drug interaction (DDI) potential of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib was characterised in vitro. 2. Rucaparib showed moderate cellular permeability, moderate human plasma protein binding (70.2%), and slow metabolism in human liver microsomes (HLMs). In HLMs, cytochrome P450 (CYP) 1A2 and CYP3A contributed to

In vitro–in vivo extrapolation (IVIVE) using human liver microsomes has been widely used to predict metabolic clearance, but some of the factors used in the process of prediction show variability for the same compound: notably, microsomal intrinsic clearance values corrected by the unbound fraction (CLint, u), physiological parameters used for scale-up, and the source of in vivo clearance data. The

Pregnane X receptor (PXR) as a ligand dependent transcription factor, is capable of regulating gene expression of cytochromes P450 and transporters involved in xenobiotic/drug metabolism and elimination. Due to the species differences in the regulatory specificity of PXR, gene regulation should not be extrapolated from mammal to fish without research data. The aim of present study was to investigate

Cytochromes P450 (CYPs) catalyze a great number of metabolic reactions that have profound effects on the biological activities of xenobiotics and endobiotics. In this study, we aimed to characterize rhythmic expressions of drug-metabolizing CYPs using synchronized hepatoma cells, and to investigate the potential roles of cis-elements of circadian clock system (E-box, D-box and RevRE or RORE) in generating

Cenerimod is a sphingosine-1-phosphate 1 receptor modulator under development for treatment of systemic lupus erythematosus. This single-centre, open-label, single-dose study investigated the mass balance and excretion routes and aimed at identifying and quantifying cenerimod metabolites in plasma, urine, and faeces after oral administration of 2 mg/100 μCi (3.7 MBq) of 14C-cenerimod. Total mean cumulative

The present study aimed to determine the effect of Hibiscus sabdariffa and Zingiber officinale on antihypertensive activity and pharmacokinetic of losartan in hypertensive rats.Hypertension was induced in rats by oral administration of L-NAME (40 mg/kg per day). Pharmacodynamics and pharmacokinetics of losartan were evaluated without and with herbal treatment in hypertensive rats.Treatment of hypertensive

(2020). Correction. Xenobiotica: Vol. 50, No. 8, pp. 1009-1009.

LLC-1903, a novel anticancer compound, was synthesized by optimizing the structure, which was derived from altering the leaving group of lobaplatin. It has an excellent in vitro anti-cancer activity, high water solubility, high stability in solution and low in vivo toxicity according to our former study. The plasma pharmacokinetics (PK) and tissue distribution of LLC-1903 and lobaplatin in rats were

1. Challenges and opportunities within peptide ADME (absorption, distribution, metabolism and elimination) were presented and discussed at the 1st peptide workshop of the Peptide ADME Discussion Group in Gothenburg, Sweden (15th of October 2018). This article summarises the presentations and discussions from this 1st workshop. The following topics were covered: Background science presentation on p

To reveal putative bioactivation pathways of diclofenac, in vitro human liver materials such as microsomal fractions and hepatocytes were used to confirm metabolic activation of diclofenac by 35S-cysteine trapping assay and covalent binding assay. Candidate human liver proteins possibly targeted by 14C-diclofenac via bioactivation were investigated using two-dimensional gel electrophoresis followed