Enantioselective in vitro ADME, absolute oral bioavailability and pharmacokinetics of (-)-lumefantrine and (+)-lumefantrine in mice.
Abstract Lumefantrine (LFN) is a chiral anti-malarial drug. Enantioselective in vitro attributes and absolute oral pharmacokinetics for (-)-LFN and (+)-LFN have been characterized in mice.No stereoselectivity was seen with either of the enantiomers when compared with rac-LFN in the executed in vitro studies (solubility, metabolic stability, protein binding, permeability and blood partitioning).Post intravenous or oral administration of rac-LFN, the AUC0-∞ and MRT of (+)-LFN was higher over (-)-LFN, which is reflected in higher clearance value for (-)-LFN.Following (-)-LFN intravenous administration to mice t...
Source: Xenobiotica - September 15, 2020 Category: Research Authors: Babulal Gabani B, Dixit A, Kiran V, Bestha RM, Balaji N, Srinivas NR, Mullangi R Tags: Xenobiotica Source Type: research

Pharmacokinetic interaction between dronedarone and ticagrelor following oral administration in rats.
The objective of the present in-vivo study was to investigate the potential interaction between dronedarone (5 and 10 mg/kg) and ticagrelor (5 and 10 mg/kg) when administered orally to rats.Forty Sprague-Dawley rats were randomly distributed into eight groups; consisting of a dronedarone only group, a ticagrelor only group, a dronedarone with ticagrelor-pretreatment group, and a ticagrelor with dronedarone-pretreatment group.Pharmacokinetic exposure (AUCinf= 1472 ng·h/mL) associated with administration of 10 mg/kg of dronedarone increased significantly, with delayed Tmax in the group that...
Source: Xenobiotica - September 11, 2020 Category: Research Authors: Kim DK, Chung SY, Kwak JH, Kim MS, Staatz CE, Lee HS, Baek IH Tags: Xenobiotica Source Type: research

Metabolism and disposition in rats, dogs, and humans of erdafitinib, an orally administered potent pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor.
This article describes in vivo biotransformation and disposition of erdafitinib following single oral dose of 3H-erdafitinib and 14C-erdafitinib to intact and bile duct-cannulated (BC) rats (4 mg/kg), 3H-erdafitinib to intact dogs (0.25 mg/kg), and 14C-erdafitinib to humans (12 mg; NCT02692677).Peak plasma concentrations of total radioactivity were achieved rapidly (Tmax: animals, 1 hour; humans, 2-3 hours). Recovery of drug-derived radioactivity was significantly slower in humans (87%, 384 hours) versus animals (rats: 91%-98%, 48 hours; dogs: 81%, 72 hours). Faeces w...
Source: Xenobiotica - September 9, 2020 Category: Research Authors: Scheers E, Borgmans C, Keung C, Bohets H, Wynant I, Poggesi I, Cuyckens F, Leclercq L, Mamidi RNVS Tags: Xenobiotica Source Type: research

Population pharmacokinetics of mycophenolic acid in pediatric patients with juvenile dermatomyositis and optimization of limited sampling strategy.
This study aimed to develop a population pharmacokinetic (PPK) model of MPA in children with juvenile dermatomyositis (JDM) and optimize the limited sampling strategy (LSS).Fifteen JDM patients treated with MMF, at a median age of 7.35 (range, 3.09 - 16.1) years, were included. Blood samples were collected at 30 minutes pre-dose, 20 minutes, 60 minutes, and 180 minutes post-dose to measure the MPA concentrations. Data were retrospectively collected from the electronic medical records. A two-compartment model with first-order absorption, lag time in absorption, and first-order elimination was dev...
Source: Xenobiotica - September 9, 2020 Category: Research Authors: Wang G, Ye Q, Huang Y, Lu J, Xu H, Li Z Tags: Xenobiotica Source Type: research

In vitro inhibition and induction of human liver cytochrome P450 enzymes by a novel anti-fibrotic drug fluorofenidone.
Abstract Fluorofenidone(AKF-PD) is an analog of pirfenidone and shows stronger antifibritic effect and lower toxicity compared to pirfenidone in preclinical studies. However, the inhibitory and inducible effects of AKF-PD on human CYP450s are unclear. The aim of this study was to evaluate the ability of AKF-PD to inhibit and induce CYP450s in vitro.In inhibition study, the inhibitory effects of CYP1A2, CYP3A4, CYP2C9, CYP2E1, CYP2C19 and CYP2D6 by AKF-PD were evaluated with the metabolic rate of probe drug of each enzyme in pooled human liver microsomes. The enzyme inducible potential of AKF-PD was evaluated by th...
Source: Xenobiotica - September 8, 2020 Category: Research Authors: Li L, Luo X, Cheng Z Tags: Xenobiotica Source Type: research

Evaluation of covalent binding of flutamide and its risk assessment using 19F-NMR.
This study aimed to provide a practical approach toward the risk assessment of hepatotoxicity induced by covalent binding before candidate selection.We focused on flutamide because it contains a trifluoromethyl group that shows a strong singlet peak by 19F-nuclear magnetic resonance (NMR) spectrometry. The covalent binding of flutamide was evaluated using quantitative NMR and its risk for hepatotoxicity was assessed by estimating the reactive metabolite (RM) burden, an index that reflects the body burden associated with reactive metabolite exposure by determining the extent of covalent binding, clinical dose, and in vivo c...
Source: Xenobiotica - September 2, 2020 Category: Research Authors: Kakutani N, Iwai T, Ohno Y, Kobayashi S, Nomura Y Tags: Xenobiotica Source Type: research

Oral antibiotics used in the treatment of chronic rhinosinusitis have limited penetration into the sinonasal mucosa: a randomized trial.
Abstract Despite the widespread prescription of antibiotics for patients with chronic rhinosinusitis (CRS), the extent to which drug distribution to the sinonasal mucosa occurs remains largely undefined.Twenty subjects undergoing functional endoscopic sinus surgery (FESS) for CRS were randomized to one of two groups: 1) doxycycline (100 mg daily for seven days) 2) roxithromycin (300 mg daily for seven days). Drug levels were measured using liquid chromatography-tandem mass spectrometry in sinonasal mucus, sinonasal tissues and serum at steady state.Doxycycline concentrations measured in the mucus wer...
Source: Xenobiotica - August 25, 2020 Category: Research Authors: Siu J, Klingler L, Wang Y, Hung CT, Jeong SH, Smith S, Tingle M, Wagner Mackenzie B, Biswas K, Douglas R Tags: Xenobiotica Source Type: research

MRP4 is responsible for the efflux transport of mycophenolic acid β-D glucuronide (MPAG) from hepatocytes to blood.
MRP4 is responsible for the efflux transport of mycophenolic acid β-D glucuronide (MPAG) from hepatocytes to blood. Xenobiotica. 2020 Aug 21;:1-28 Authors: Berthier J, Benmameri M, Sauvage FL, Fabre G, Chantemargue B, Arnion H, Marquet P, Trouillas P, Picard N, Saint-Marcoux F Abstract Mycophenolic acid (MPA) has become a cornerstone of immunosuppressive therapy, in particular for transplant patients. In the gastrointestinal tract, the liver and the kidney, MPA is mainly metabolized into phenyl-β-D glucuronide (MPAG). Knowledge about the interactions between MPA/MPAG and membrane transporter...
Source: Xenobiotica - August 21, 2020 Category: Research Authors: Berthier J, Benmameri M, Sauvage FL, Fabre G, Chantemargue B, Arnion H, Marquet P, Trouillas P, Picard N, Saint-Marcoux F Tags: Xenobiotica Source Type: research

Genetic variants of UDP-glucuronosyltransferases 1A1, 1A6, and 1A9 in cynomolgus and rhesus macaques.
Abstract 1. In the cynomolgus macaque, UDP-glucuronosyltransferases (UGTs) 1As have similar molecular and enzymatic characteristics to those of their human orthologs. However, genetic polymorphisms in major cynomolgus UGT1A1/6/9 have not been investigated. 2. We re-sequenced UGT1A1, UGT1A6, and UGT1A9 in 186 cynomolgus macaques (bred in Cambodia, China, or Indonesia) and 54 rhesus macaques and found 15, 13, and 26 non-synonymous variants, respectively. 3. Of these UGT1A1, UGT1A6, and UGT1A9 variants, respectively, 10, 9, and 12 were unique to cynomolgus macaques; 4, 1, and 2 were unique to rhesus macaques; and 1, ...
Source: Xenobiotica - August 19, 2020 Category: Research Authors: Uno Y, Mikami T, Tsukazaki Y, Nakanishi Y, Murayama N, Ikushiro S, Tsusaki H, Yamazaki H Tags: Xenobiotica Source Type: research

Main contribution of UGT1A1 and CYP2C9 in the metabolism of UR-1102, a novel agent for the treatment of gout.
Abstract UR-1102, a novel urisocuric agent for treating gout, has been confirmed to exhibit a pharmacological effect in patients. We clarified its metabolic pathway, estimated the contribution of each metabolic enzyme, and assessed the impact of genetic polymorphisms using human in vitro materials.Glucuronide, sulfate, and oxidative metabolites of UR-1102 were detected in human hepatocytes.The intrinsic clearance by glucuronidation or oxidation in human liver microsomes was comparable, but sulfation in the cytosol was much lower, indicating that the rank order of contribution was glucuronidation ≥&thinsp...
Source: Xenobiotica - August 19, 2020 Category: Research Authors: Yamane M, Igarashi F, Yamauchi T, Nakagawa T Tags: Xenobiotica Source Type: research

The influence of multiple oral administration on the pharmacokinetics and distribution profile of dalcetrapib in rats.
Abstract We investigated the influence of multiple oral administration on the accumulation of dalcetrapib (JTT-705/RO4607381), a novel cholesteryl ester transfer protein inhibitor, in rats.It is well known that orally administered dalcetrapib is rapidly hydrolysed to its active form, which has a sulfhydryl group, in the body. The active form then binds covalently to endogenous thiols via mixed disulfide bonds.Following multiple once daily oral administration of 14C-dalcetrapib for seven days to rats, the concentration of radioactivity in the plasma and almost all tissues reached the steady state by day 4. At 24&th...
Source: Xenobiotica - August 12, 2020 Category: Research Authors: Takubo H, Ishikawa T, Taniguchi T, Iwanaga K, Nomura Y Tags: Xenobiotica Source Type: research

Characterization of plasma protein binding in two mouse models of humanized liver, PXB mouse and humanized TK-NOG mouse.
Abstract The unbound fractions in plasma (fup) in two mouse models of humanized liver mice, PXB and humanized TK-NOG mice, were compared with human fup values using equilibrium dialysis method. A good relationship between fup values obtained from PXB mice and humans was observed; the fup of 34/39 compounds (87.2%) in PXB mice were within 3-fold of human fup. In contrast, a weak correlation was observed between human and humanized TK-NOG mouse fup values; the fup of 15/24 compounds (62.5%) in humanized TK-NOG mice were within 3-fold of human fup.As different profiles of plasma protein binding (PPB) profiles were ob...
Source: Xenobiotica - August 11, 2020 Category: Research Authors: Miyamoto M, Kosugi Y, Iwasaki S, Chisaki I, Nakagawa S, Amano N, Hirabayashi H Tags: Xenobiotica Source Type: research

Kinetics of metabolism of deltamethrin and cis- and trans-permethrin in vitro. Studies using rat and human liver microsomes, isolated rat hepatocytes and rat liver cytosol.
This study demonstrates that the nonspecific binding of these highly lipophilic compounds needs to be taken into account in order to obtain accurate estimates of rates of in vitro metabolism of these pyrethroids. While DLM is rapidly metabolised in vitro, the hepatocyte membrane does not appear to represent a barrier to the absorption and hence subsequent hepatic metabolism of this pyrethroid. PMID: 32757971 [PubMed - as supplied by publisher] (Source: Xenobiotica)
Source: Xenobiotica - August 6, 2020 Category: Research Authors: Price RJ, Scott MP, Cantrill C, Higgins LG, Moreau M, Yoon M, Clewell HJ, Creek MR, Osimitz TG, Houston JB, Lake BG Tags: Xenobiotica Source Type: research

Evaluation of the changes in exposure to thiol compounds in chronic kidney disease patients using the PBPK model.
Abstract Targeted covalent inhibitors designed to bind covalently to a specific molecular target have recently been a focus of drug development. Among these inhibitors, thiol compounds bind covalently to endogenous thiols in the body through a process involving disulfide bonds.We investigated the predictability of changes in the exposure to captopril, tiopronin, the active form of dalcetrapib and the active metabolite of prasugrel, R-138727, all of which have a sulfhydryl group, in moderate and severe chronic kidney disease (CKD) patients using a constructed PBPK model.The changes in the exposure to captopril, tio...
Source: Xenobiotica - August 3, 2020 Category: Research Authors: Takubo H, Taniguchi T, Iwanaga K, Nomura Y Tags: Xenobiotica Source Type: research

Comparative assessment for rat strain differences in metabolic profiles of 14 drugs in Wistar Han and Sprague Dawley hepatocytes.
Abstract 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 metabolic clearances of SD and WH strains, suggesting that only one strain can be confidently used for the evaluation of hepatic clearance. Neither strain of rat was preferable over the other to cover ...
Source: Xenobiotica - July 27, 2020 Category: Research Authors: Wang W, Teresa M, Cai J, Zhang C, Wong S, Yan Z, Khojasteh SC, Zhang D Tags: Xenobiotica Source Type: research

An in vitro approach to simulate the process of 5-fluorouracil degradation with dihydropyrimidine dehydrogenase: the process in accordance to the first-order kinetic reaction.
In conclusion, mixing 5-FU with blank matrix can simulate the process of 5-FU degradation with DPD. PMID: 32686977 [PubMed - as supplied by publisher] (Source: Xenobiotica)
Source: Xenobiotica - July 20, 2020 Category: Research Authors: Qin W, Wang X, Chen W, Du W, Zhang D, Zhang X, Li P Tags: Xenobiotica Source Type: research

Metabolism of bifenthrin, β-cyfluthrin, λ-cyhalothrin, cyphenothrin and esfenvalerate by rat and human cytochrome P450 and carboxylesterase enzymes.
This study demonstrates that the ability of male rats to metabolise these pyrethroids by hepatic CYP and CES enzymes and plasma CES enzymes increases with age. In all instances, apparent intrinsic clearance values were lower in 15 than in 90 day old rats.All pyrethroids were metabolised by some of the human expressed CYP enzymes studied and apart from BIF were also metabolised by CES enzymes. PMID: 32672501 [PubMed - as supplied by publisher] (Source: Xenobiotica)
Source: Xenobiotica - July 16, 2020 Category: Research Authors: Hedges L, Brown S, MacLeod AK, Moreau M, Yoon M, Creek MR, Osimitz TG, Lake BG Tags: Xenobiotica Source Type: research

Plasma protein binding, metabolism, reaction phenotyping and toxicokinetic studies of fenarimol after oral and intravenous administration in rats.
Abstract 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%, suggesting that FNL is a highly protein bound fungicide. The predicted in vivo hepatic clearance of FNL in rats and humans was estimated to be 36.71 mL/min/kg and 14.39 mL/min/kg, respectively, ...
Source: Xenobiotica - July 14, 2020 Category: Research Authors: Karsauliya K, Sonker AK, Bhateria M, Taneja I, Srivastava A, Sharma M, Singh SP Tags: Xenobiotica Source Type: research

Understanding metabolism related differences in ocular efficacy of MGV354.
Abstract 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 to produce similar results in patients with ocular hypertension or open-angle glaucoma.With an objective of explaining the lack of efficacy in the clinic, we attempted to study whether human metabolism w...
Source: Xenobiotica - July 14, 2020 Category: Research Authors: Dumouchel JL, Argikar UA, Adams CM, Prasanna G, Ehara T, Kim S, Breen C, Mogi M Tags: Xenobiotica Source Type: research

Nonadditivity in Human Microsomal Drug Metabolism Revealed in a Study with Coumarin 152, a Polyspecific Cytochrome P450 Substrate.
Abstract 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. The metabolism of C152 by the individual P450 species was characterized using the microsomes containing cDNA-expressed enzymes. C152 metabolism in human liver microsomes (HLM) was studied in a preparation w...
Source: Xenobiotica - July 14, 2020 Category: Research Authors: Dangi B, Davydova NY, Vavilov NE, Zgoda VG, Davydov DR Tags: Xenobiotica Source Type: research

Characterization of hydrocoptisonine metabolites in human liver microsomes using a high-resolution quadrupole-orbitrap mass spectrometer.
Abstract 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 conjugates, using a high-resolution quadrupole-orbitrap mass spectrometer. The major metabolic pathway was the O-demethylation and mono-hydroxylation of hydrocoptisonine in HLMs. Notably, M3 metabolite was O-...
Source: Xenobiotica - July 13, 2020 Category: Research Authors: Choi SM, Kim Y, Lee J, Kim JH, Lee T, Min BS, Kim JA, Lee S Tags: Xenobiotica Source Type: research

Pharmacokinetics of levofloxacin after single intravenous and oral administration, and its interaction with sucralfate in mixed-breed dogs.
recalde C Abstract 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.After iv of levofloxacin, the mean (± SD) of AUC0-24, Vz, t½λz and MRT, were 19.05 ± 6.4 µg-h/ml, 2.43 ± 0.5 L/...
Source: Xenobiotica - July 6, 2020 Category: Research Authors: Urzúa N, Messina MJ, Caverzan M, Prieto G, Lüders C, Errecalde C Tags: Xenobiotica Source Type: research

Modelled plasma concentrations of pemafibrate with co-administered typical cytochrome P450 inhibitors clopidogrel, fluconazole, or clarithromycin predicted by physiologically based pharmacokinetic modelling in virtual populations.
Abstract 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 established for co-administration of pemafibrate with OATP1B1 inhibitors.This PBPK model was validated in the current study using reported maximum pemafibrate plasma concentrations and areas under the curve...
Source: Xenobiotica - July 6, 2020 Category: Research Authors: Ogawa SI, Shimizu M, Yamazaki H Tags: Xenobiotica Source Type: research

Impact of quercetin on pharmacokinetics of quetiapine: Insights from in-vivo studies in Wistar rats.
Abstract 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 through liquid chromatography-tandem mass spectrometry.The results showed a significant (p
Source: Xenobiotica - July 5, 2020 Category: Research Authors: Bhutani P, Ranjanna PK, Paul AT Tags: Xenobiotica Source Type: research

Impact of single nucleotide polymorphisms (R132Q and W120R) on the binding affinity and metabolic activity of CYP2C19 toward some therapeutically important substrates.
Abstract 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, lansoprazole and omeprazole) was investigated. Resonance Raman and UV-VIS spectroscopies revealed a minimal effect of SNP mutations on the heme structure. However, the mutation greatly affected the drug metaboli...
Source: Xenobiotica - June 24, 2020 Category: Research Authors: Derayea SM, Tsujino H, Oyama Y, Ishikawa Y, Yamashita T, Uno T Tags: Xenobiotica Source Type: research

Meeting report: 2nd Workshop of the Peptide ADME Discussion Group.
This article summarises the presentations and discussions from this workshop.The following topics were covered: Peptide drug-drug interactions (DDIs)Regulatory perspectives on peptide ADME studiesBioavailability of therapeutic peptides impacted by metabolism and oligomerization in the subcutaneous compartmentRegulated bioanalysis of parent peptide and active metabolites by immunoaffinity LC-MS/MSPeptide radiopharmaceutical development. PMID: 32571130 [PubMed - as supplied by publisher] (Source: Xenobiotica)
Source: Xenobiotica - June 22, 2020 Category: Research Authors: Sonesson A, Bjørnsdottir I, Christensen JK Tags: Xenobiotica Source Type: research

Diversifying selection detected in only a minority of xenobiotic-metabolizing CYP1-3 genes among primate species.
Abstract 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) greater variability in gene-copy number and (2) more evidence of diversifying selection and, especially on codons that encode the substrate-recognition sites (SRSs) for the final enzymes.Counter to our first ...
Source: Xenobiotica - June 19, 2020 Category: Research Authors: Chaney ME, Romine MG, Piontkivska H, Tosi AJ Tags: Xenobiotica Source Type: research

Inhibitory effect of sixteen pharmaceutical excipients on six major organic cation and anion uptake transporters.
Abstract 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 polypeptide 1B1 and 1B3 (hOATP1B1 and hOATP1B3).The inhibitory effects and mechanisms of excipients on transporters were investigated using in vitro uptake studies, cell viability assays, concentration-depen...
Source: Xenobiotica - June 16, 2020 Category: Research Authors: Ma R, Li G, Wang X, Bi Y, Zhang Y Tags: Xenobiotica Source Type: research

Development and validation of a LC-MS/MS method for simultaneous determination of TQ-A3326 and its major metabolites in human plasma, urine and feces: application to pharmacokinetic assay.
Abstract 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). Plasma, feces and urine samples were extracted through protein precipitation. A rapid and sensitive LC-MS/MS method was successfully developed and applied to assess the PK properties of TQ-A3326.The AUC0-...
Source: Xenobiotica - June 10, 2020 Category: Research Authors: Xu B, Deng Y, Li X, Guo S, Gao Z, Xu W, Li Y, Zhang P, Zhang L, Huang J Tags: Xenobiotica Source Type: research

The use of inactivated brain homogenate to determine the in  vitro fraction unbound in brain for unstable compounds.
The use of inactivated brain homogenate to determine the in vitro fraction unbound in brain for unstable compounds. Xenobiotica. 2020 Jun 05;:1-8 Authors: Nirogi R, Molgara P, Bhyrapuneni G, Manoharan A, Padala NP, Palacharla VRC Abstract 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...
Source: Xenobiotica - June 5, 2020 Category: Research Authors: Nirogi R, Molgara P, Bhyrapuneni G, Manoharan A, Padala NP, Palacharla VRC Tags: Xenobiotica Source Type: research

Disposition and Metabolism of 2,2'-Dimorpholinodiethyl Ether in Sprague Dawley Rats and B6C3F1/N Mice after Oral, Intravenous Administration, and Dermal Application.
Abstract 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 rats, following a single oral administration, [14C]DMDEE was well-absorbed and excreted rapidly and extensively via urine (75-93%) and some in feces (∼ 4-8%). The total radioactivity in tissues at 24&...
Source: Xenobiotica - June 5, 2020 Category: Research Authors: Waidyanatha S, McDonald JD, Sanders JM, Doyle-Eisele M, Moeller BC, Garner CE Tags: Xenobiotica Source Type: research

Disposition and metabolism of antibacterial agent, triclocarban, in rodents; a species and route comparison.
Abstract 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 was excreted in bile suggesting some of the fecal excretion is from the absorbed dose which was excreted to the intestine via bile.The tissue retention of radioactivity was low in male rats (24 h, 3...
Source: Xenobiotica - June 5, 2020 Category: Research Authors: Waidyanatha S, Black SR, Patel PR, Watson SL, Snyder RW, Sutherland V, Stanko J, Fennell TR Tags: Xenobiotica Source Type: research

LncRNA HOTAIR modulates the expression of OATP1B1 in HepG2 cells by sponging miR-206/miR-613.
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 RNA mechanism was validated by bioinformatics analysis and a dual-luciferase reporter gene assay.Our results showed that over- or under-expression of LncRNA HOTAIR correspondingly significantly increased or decreased the protein level of OATP1B1 in HepG2 cells, while no significant change in OATP1...
Source: Xenobiotica - June 2, 2020 Category: Research Authors: Xu Y, Hu J, Zhang Y, Liu M, Zhang H, Xia C, Xiong Y Tags: Xenobiotica Source Type: research

Referee acknowledgements.
Authors: PMID: 32301396 [PubMed - in process] (Source: Xenobiotica)
Source: Xenobiotica - April 19, 2020 Category: Research Tags: Xenobiotica Source Type: research

Correction.
Authors: PMID: 32151212 [PubMed - in process] (Source: Xenobiotica)
Source: Xenobiotica - March 11, 2020 Category: Research Tags: Xenobiotica Source Type: research

Effects of multidose simvastatin co-administration on pharmacokinetic profile of apatinib in rats by UPLC-MS/MS.
Abstract Apatinib, a small molecule anti-angiogenic tyrosine kinase inhibitor (TKI), 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 CYP3A4, they are likely to interact. Therefore, the potential effect of SV co-administration on pharmacokinetics of apatinib in Sprague-Dawley male rats is demonstrated for the first time.Sixteen rats were randomly divided into two groups (n = 8), group B (2 mg/kg SV orally co-administrated for 7 days) and the c...
Source: Xenobiotica - March 9, 2020 Category: Research Authors: Gao J, Ren H, Feng Z, Chen S, Liang Y, Liu W, Zhou Q, Wang M Tags: Xenobiotica Source Type: research

Evaluation of in vitro absorption, distribution, metabolism, and excretion and assessment of drug-drug interaction of rucaparib, an orally potent poly(ADP-ribose) polymerase inhibitor.
Abstract The absorption, distribution, metabolism, elimination, and drug-drug interaction (DDI) potential of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib was characterized in vitro.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 the metabolism of rucaparib to its major metabolite M324 with estimated fractions of metabolism catalyzed by CYP (fm,CYP) of 0.27 and 0.64, respectively. Rucaparib reversibly inhibited CYP1A2, CYP2C9, CYP2C19, CYP2D6...
Source: Xenobiotica - March 4, 2020 Category: Research Authors: Liao M, Jaw-Tsai S, Beltman J, Simmons AD, Harding TC, Xiao JJ Tags: Xenobiotica Source Type: research

In vitro-in vivo extrapolation of metabolic clearance using human liver microsomes: Factors showing variability and their normalization.
Abstract 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 purpose of this study was to assess the correlation between in vitro and in vivo CLint with a focus on factors showing variability using four cytochrome P450 (CYP) 3A substrates.We surveyed in vivo clearance val...
Source: Xenobiotica - March 3, 2020 Category: Research Authors: Morita K, Kato M, Kudo T, Ito K Tags: Xenobiotica Source Type: research

Metabolism and disposition of corylifol A from Psoralea corylifolia: metabolite mapping, isozyme contribution, species differences, and identification of efflux transporters for corylifol A-O-glucuronide in HeLa1A1 cells.
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 were evaluated in HLM, expressed CYPs and UGTs. Chemical inhibitors and shRNA-mediated gene siliencing of multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP) were performed to assess the roles of transporters in CA disposition.Three oxidated metabolites (M1-M3...
Source: Xenobiotica - March 2, 2020 Category: Research Authors: Li Y, Xu J, Xu C, Qin Z, Li S, Hu L, Yao Z, Gonzalez FJ, Yao X Tags: Xenobiotica Source Type: research

Effects of 27 natural products on drug metabolism genes in channel catfish (Ictalurus punctatus) cell line.
Abstract 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 the effect of 27 natural products on PXR, CYP3A30 and MDR1 genes in channel catfish (Ietalurus punetaus) kidney cells (CC-K). The results showed that bisdemethoxycurcumin, glycyrrhetnic acid, rotenone, artemis...
Source: Xenobiotica - March 2, 2020 Category: Research Authors: Wang Z, Liu Y, Ai X, Zhong L, Han G, Song J, Yang Q, Jing D Tags: Xenobiotica Source Type: research

Identification of rhythmic human CYPs and their circadian regulators using synchronized hepatoma cells.
In conclusion, rhythmic expressions of five human CYPs (CYP1A2, 2B6, 2C8, 2E1 and 3A4) are generated and regulated by E-box-, D-box-, and/or RevRE-acting clock components. Our findings may have implications for understanding chronopharmacokinetic events in humans. PMID: 32118505 [PubMed - as supplied by publisher] (Source: Xenobiotica)
Source: Xenobiotica - March 2, 2020 Category: Research Authors: Chen M, Zhou C, Zhang T, Wu B Tags: Xenobiotica Source Type: research

Absorption, distribution, metabolism, and excretion of cenerimod, a selective S1P1 receptor modulator in healthy subjects.
Abstract 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 recovery was 84% of the administered dose (58-100% in faeces and 4.6-12% in urine). In a 0-504 h cross-subject area under the curve plasma pool, cenerimod and two metabolites were detecte...
Source: Xenobiotica - February 27, 2020 Category: Research Authors: Boof ML, van Lier JJ, English S, Fischer H, Ufer M, Dingemanse J Tags: Xenobiotica Source Type: research

Correction.
Authors: PMID: 32098559 [PubMed - as supplied by publisher] (Source: Xenobiotica)
Source: Xenobiotica - February 25, 2020 Category: Research Tags: Xenobiotica Source Type: research

Pharmacokinetics and tissue distribution in rats of a novel anticancer platinum compound LLC-1903.
Abstract 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 determined after intravenous administration of a single dose (0.06 mmol/kg body weight). Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure the concentration of platinum ...
Source: Xenobiotica - February 19, 2020 Category: Research Authors: Li Y, Meng F, Chen Z, Han F, He D, Hao Y, Gao A, Jiang J, Wang Z, Liu W, Liu Q Tags: Xenobiotica Source Type: research

CYP2C19 and CYP3A4 Activity and ADP-induced Platelet Reactivity in Prasugrel- or Ticagrelor-treated STEMI Patients: Monocentric Study in PRAGUE-18 Trial Participants.
plíchal Z, Moťovská Z, Juřica J Abstract 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-elevations 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 treatment with prasugrel (n = 51) or ticagrelor (n = 46). Metabolic activity of CYP2C19 and CYP3A4 was assessed by the r...
Source: Xenobiotica - February 17, 2020 Category: Research Authors: Máchal J, Hlinomaz O, Kostolanská K, Peš O, Máchalová A, Šplíchal Z, Moťovská Z, Juřica J Tags: Xenobiotica Source Type: research

Meeting report: 1st Workshop of the Peptide ADME Discussion Group.
This article summarises the presentations and discussions from this 1st workshop.The following topics were covered:Background science presentation on peptidasesPresentation of various peptide ADME packagesPeptide drug-drug interactions (DDI). PMID: 32048540 [PubMed - as supplied by publisher] (Source: Xenobiotica)
Source: Xenobiotica - February 12, 2020 Category: Research Authors: Sonesson A, Brady K, Bjørnsdottir I, Christensen JK Tags: Xenobiotica Source Type: research

Effect of Hibiscus sabdariffa and Zingiber officinale on the antihypertensive activity and pharmacokinetic of losartan in hypertensive rats.
In conclusion, both the investigated herbs significantly increased the antihypertensive effect and plasma concentration of losartan in L-NAME induced hypertensive rats. The current study predicted that the herb-drug interaction between H. sabdariffa-losartan and Z. officinale-losartan could occur; hence these results in rats may warrant further studies in humans, either in humans or in in vitro human liver microsomes. PMID: 32048541 [PubMed - as supplied by publisher] (Source: Xenobiotica)
Source: Xenobiotica - February 12, 2020 Category: Research Authors: Ahad A, Raish M, Bin Jardan YA, Alam MA, Al-Mohizea AM, Al-Jenoobi FI Tags: Xenobiotica Source Type: research

Bioactivation of diclofenac in human hepatocytes and the proposed human hepatic proteins modified by reactive metabolites.
Abstract 1. To reveal putative bioactivation pathways of diclofenac, in vitro human liver materials such as microsomal fractions and hepatocytes were employed 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 by detection of remaining radioactivity on the modified proteins with bio-imaging analyzer.2. In the 35S-cysteine trapping assay, two and one adducts with 35S-cysteine were observed in NADPH-fortified an...
Source: Xenobiotica - February 10, 2020 Category: Research Authors: Inoue K, Mizuo H, Ishida T, Komori T, Kusano K Tags: Xenobiotica Source Type: research

In vitro effect of pachymic acid on the activity of Cytochrome P450 enzymes.
Abstract 1. Pachymic acid is a wildly used traditional Chinese medicine with various pharmacological features.2.The effect of pachymic acid on the activity of eight major CYP isoforms was investigated in human liver microsomes.3. The effects of pachymic acid on eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) were investigated in vitro using human liver microsomes (HLMs), and the enzyme kinetic parameters were calculated.4. The activity of CP3A4, 2E1, and 2C9 was inhibited by pachymic acid in a concentration-dependent manner with IC50 values of 15.04, 27.95, and 24.22 μM,...
Source: Xenobiotica - February 6, 2020 Category: Research Authors: Ding B, Ji X, Sun X, Zhang T, Mu S Tags: Xenobiotica Source Type: research

Wogonin glucuronidation in liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice.
Abstract 1. Wogonin, one of the flavonoids isolated from Scutellaria baicalensis, exhibits some beneficial bioactivities, including anti-inflammatory and anticancer effects, and is metabolized into glucuronide by UDP-glucuronosyltransferase (UGT) enzymes in humans. In the present study, wogonin glucuronidation was examined in the liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice using a kinetic analysis.2. The kinetics of wogonin glucuronidation by liver microsomes followed the biphasic model in all species examined. CLint values (x-intercept) based on v versus V/[S] plots were rats &...
Source: Xenobiotica - January 31, 2020 Category: Research Authors: Hanioka N, Isobe T, Tanaka-Kagawa T, Ohkawara S Tags: Xenobiotica Source Type: research