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Single dose pharmacokinetics of topical iodiconazole creams in healthy Chinese volunteers Xenobiotica (IF 1.902) Pub Date : 2021-01-22 Lili Wu; Ke Zhou; Wenkai Zong; Yun Chen; Chunquan Sheng
Abstract In this study, the pharmacokinetics of new triazole antifungal iodiconzole creams at target sites after single-dose topical application was investigated. 30 healthy Chinese volunteers were randomly divided into three groups after being stratified by sex, each group was given a single topical dose of 1%, 2%, 4% iodiconazole cream (0.4 g). Stratum corneum (SC) samples of treated sites were collected
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Differential in vitro interactions of the Janus kinase inhibitor ruxolitinib with human SLC drug transporters Xenobiotica (IF 1.902) Pub Date : 2021-01-18 Arnaud Bruyère; Marc Le Vée; Elodie Jouan; Stephanie Molez; Anne T. Nies; Olivier Fardel
Abstract Interactions of the Janus kinase (JAK) inhibitor ruxolitinib with solute carriers (SLCs) remain incompletely characterized. The present study was therefore designed to investigate this issue. The interactions of ruxolitinib with SLCs were analyzed using transporter-overexpressing HEK293 cells. Substrate accumulation was detected by spectrofluorimetry, LC-MS/MS spectrometry or scintillation
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Methyl-hydroxylation and subsequent oxidation to produce carboxylic acid is the major metabolic pathway of tolbutamide in chimeric TK-NOG mice transplanted with human hepatocytes Xenobiotica (IF 1.902) Pub Date : 2021-01-18 Shotaro Uehara; Nao Yoneda; Yuichiro Higuchi; Hiroshi Yamazaki; Hiroshi Suemizu
Abstract Tolbutamide is an oral anti-hyperglycaemic agent used to treat non-insulin–dependent diabetes mellitus with species-dependent metabolic profiles. In this study, we investigated tolbutamide metabolism in chimeric TK-NOG mice transplanted with human hepatocytes (humanised-liver mice). Substantial 4-hydroxytolbutamide and 4-carboxytolbutamide production was observed in hepatocytes from humanised-liver
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Human total clearance values and volumes of distribution of typical human cytochrome P450 2C9/19 substrates predicted by single-species allometric scaling using pharmacokinetic data sets from common marmosets genotyped for P450 2C19 Xenobiotica (IF 1.902) Pub Date : 2021-01-17 Shogo Matsumoto; Shotaro Uehara; Hidetaka Kamimura; Hiroshi Ikeda; Satoshi Maeda; Machiko Hattori; Megumi Nishiwaki; Kazuhiko Kato; Hiroshi Yamazaki
Abstract Common marmosets (Callithrix jacchus) are small non-human primates that genetically lack cytochrome P450 2C9 (CYP2C9). Polymorphic marmoset CYP2C19 compensates by mediating oxidations of typical human CYP2C9/19 substrates. Twenty-four probe substrates were intravenously administered in combinations to marmosets assigned to extensive or poor metaboliser (PM) groups by CYP2C19 genotyping. Eliminations
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In vitro metabolism of HMTD and blood stability and toxicity of peroxide explosives (TATP and HMTD) and in canines and humans Xenobiotica (IF 1.902) Pub Date : 2021-01-13 Michelle D. Gonsalves; Lindsay McLennan; Angela L. Slitt; James L. Smith; Jimmie C. Oxley
Abstract Triacetone triperoxide (TATP) and hexamethylene triperoxide diamine (HMTD) are prominent explosive threats. Mitigation of peroxide explosives is a priority among the law enforcement community, with canine (K9) units being trained to recognize the scent of peroxide explosives. Herein, the metabolism, blood distribution and toxicity of peroxide explosives is investigated. HMTD metabolism studies
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Genetic Variants of Aldehyde Oxidase (AOX) 1 in Cynomolgus and Rhesus Macaques Xenobiotica (IF 1.902) Pub Date : 2021-01-12 Yasuhiro Uno; Shotaro Uehara; Norie Murayama; Hiroshi Yamazaki
Abstract The cynomolgus macaque is a non-human primate species widely used in drug metabolism studies. Despite the importance of genetic polymorphisms in cytosolic aldehyde oxidase (AOX) 1 in humans, genetic variants have not been investigated in cynomolgus or rhesus macaques. Genetic variants in AOX1 were identified and allele frequencies were assessed using the genomes of 24 cynomolgus and 8 rhesus
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Assessment of pharmacokinetic mycophenolic acid clearance models using Monte Carlo numerical analysis Xenobiotica (IF 1.902) Pub Date : 2021-01-08 Aleksandra Catić-Đorđević; Ivan Pavlović; Ana Spasić; Nikola Stefanović; Dragana Pavlović; Ivana Damnjanović; Branka Mitić; Radmila Veličković-Radovanović
Abstract Previously, we performed population pharmacokinetic analysis and indicated age, mycophenolate mofetil (MMF)/mycophenolic acid (MPA) daily dose, and presence of nifedipine in patient therapy as significant predictors of MPA apparent clearance (CL/F) variability. This study aimed to determine the reliability of previously published population pharmacokinetic models derived from similar studies
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Pharmacokinetics, Metabolism, and Excretion of Licogliflozin, a Dual Inhibitor of SGLT1/2, in Rats, Dogs, and Humans Xenobiotica (IF 1.902) Pub Date : 2021-01-08 Lydia Wang-Lakshman; Anisha E. Mendonza; Roland Huber; Markus Walles; YanLing He; Venkateswar Jarugula
Abstract: The absorption, metabolism, and excretion (AME) of licogliflozin, a sodium-glucose co-transporters (SGLTs) 1 and 2 inhibitor, were studied in male rats, dogs, and healthy male volunteers and reported. Oral absorption of licogliflozin was rapid (tmax < 1 hr) with absorption estimated at 87%, 100% and 77% in rats, dogs and humans, respectively. The excretion of licogliflozin-related radioactivity
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Verification of a cocktail approach for quantitative drug–drug interaction assessment: a comparative analysis between the results of a single drug and a cocktail drug Xenobiotica (IF 1.902) Pub Date : 2021-01-04 Motoyasu Miura; Shinya Uchida; Shimako Tanaka; Chiaki Kamiya; Naoki Katayama; Akio Hakamata; Keiichi Odagiri; Naoki Inui; Junichi Kawakami; Hiroshi Watanabe; Noriyuki Namiki
Abstract A cocktail approach is a method to comprehensively evaluate the activity of cytochrome P450 enzymes (CYPs) by co-administering multiple CYP substrates. This is the first report that compares the results from a cocktail study to a single substrate separate administration study (single study) with concomitant administration of CYP inducers/inhibitors. The validity of a cocktail study for use
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Comprehensive metabolism study of swertiamarin in rats using ultra high-performance liquid chromatography coupled with quadrupole-exactive orbitrap mass spectrometry Xenobiotica (IF 1.902) Pub Date : 2020-12-26 Beibei Ma; Tianyu Lou; Tingting Wang; Ruiji Li; Jinhui Liu; Shangyue Yu; Yudong Guo; Zhibin Wang; Jing Wang
Abstract: Swertiamarin, a natural ingredient with potent pharmacological activities in the iridoid glycoside family, had been reported to have significant therapeutic effects on a variety of human diseases. In this study, a systematic and efficient strategy based on UHPLC-Q-Exactive Orbitrap mass spectrometry was established to reveal the metabolic profile of swertiamarin in rat urine, plasma, and
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Liquid chromatography-tandem mass spectrometry analysis of oxidation of 2′-, 3′-, 4′- and 6-hydroxyflavanones by human cytochrome P450 enzymes Xenobiotica (IF 1.902) Pub Date : 2020-10-23 Tsutomu Shimada; Haruna Nagayoshi; Norie Murayama; Shigeo Takenaka; Jun Katahira; Vitchan Kim; Donghak Kim; Masayuki Komori; Hiroshi Yamazaki; F. Peter Guengerich
Abstract 2′-Hydroxyflavanone (2′OHFva), 3′OHFva, 4′OHFva, and 6OHFva, the major oxidative products of flavanone by human cytochrome P450 (P450, CYP) enzymes, were studied in regard to further oxidation by human CYP1A1, 1A2, 1B1.1, 1B1.3, and 2A6. The products formed were analyzed with LC-MS/MS and characterized by their positive ion fragmentations on mass spectrometry. Several di-hydroxylated flavanone
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Role of human flavin-containing monooxygenase (FMO) 5 in the metabolism of nabumetone: Baeyer–Villiger oxidation in the activation of the intermediate metabolite, 3-hydroxy nabumetone, to the active metabolite, 6-methoxy-2-naphthylacetic acid in vitro Xenobiotica (IF 1.902) Pub Date : 2020-11-16 Kaori Matsumoto; Tetsuya Hasegawa; Kosuke Ohara; Tomoyo Kamei; Junichi Koyanagi; Masayuki Akimoto
Abstract Nabumetone (NAB) is a non-steroidal anti-inflammatory drug used clinically, and its biotransformation includes the major active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA). One of the key intermediates between NAB and 6-MNA may be 3-hydroxy nabumetone (3-OH-NAB). The aim of the present study was to investigate the role of flavin-containing monooxygenase (FMO) isoform 5 in the formation
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Preclinical in vitro and in vivo pharmacokinetic properties of danicamtiv, a new targeted myosin activator for the treatment of dilated cardiomyopathy Xenobiotica (IF 1.902) Pub Date : 2020-11-16 Mark P. Grillo; Svetlana Markova; Marc Evanchik; Marc Trellu; Patricia Moliner; Priscilla Brun; Anne Perreard-Dumaine; Pascale Vicat; James P. Driscoll; Tim J. Carlson
Abstract Dilated cardiomyopathy (DCM) is a disease of the myocardium defined by left ventricular enlargement and systolic dysfunction leading to heart failure. Danicamtiv, a new targeted myosin activator designed for the treatment of DCM, was characterised in in vitro and in vivo preclinical studies. Danicamtiv human hepatic clearance was predicted to be 0.5 mL/min/kg from in vitro metabolic stability
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The permeability characteristics and interaction of main components from Si-Ni-San in a MDCK epithelial cell monolayer model. Xenobiotica (IF 1.902) Pub Date : 2020-12-02 Ruonan Chen,Chenlin Shen,Qingqing Xu,Yaru Liu,Bo Li,Cheng Huang,Taotao Ma,Xiaoming Meng,Maomao Wu,Jun Li
Abstract 1. Si-Ni-San (SNS) possesses extensive therapeutic effects, however, the extent to which main components are absorbed and the mechanisms involved are controversial. 2. In this study, MDCK cell model was used to determine the permeability characteristics and interaction between the major components of Si-Ni-San, including saikosaponin a, paeoniflorin, naringin and glycyrrhizic acid. 3. The
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Preliminary in vitro assessment of pharmacokinetic drug-drug interactions of EST64401 and EST64514, two sigma-1 receptor antagonists Xenobiotica (IF 1.902) Pub Date : 2020-12-22 Raquel F. Reinoso; Sandra Yeste; Eva Ayet; María José Pretel; Ariadna Balada; María Teresa Serafini
Abstract EST64401 and EST64514 are two selective sigma-1 receptor ligands which showed a good profile in a lead optimization process for oral pain treatment. Their potential for pharmacokinetic-based drug-drug interactions was assessed to anticipate clinical interactions. Both compounds showed a low potential for CYP inhibition with percentages of inhibition <50% at 1 µM in recombinant human CYPs (CYP1A2
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Expression of cytochrome P450 isozyme transcripts and activities in human livers Xenobiotica (IF 1.902) Pub Date : 2020-12-22 Jie Liu; Yuan-Fu Lu; J. Christopher Corton; Curtis D. Klaassen
Abstract Individual differences in cytochrome P450 (CYP) enzymes contribute to responses to drugs and environmental chemicals. The expression of CYPs are influenced by sex, age and ethnicity. Human CYP studies are often conducted with human liver microsomes and liver cells to evaluate chemical induction and drug interactions. However, the basal or constitutive expression of CYP transcripts and enzyme
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Inhibitory effect of ketoconazole, quinidine and 1-aminobenzotriazole on pharmacokinetics of l-tetrahydropalmatine and its metabolite in rats Xenobiotica (IF 1.902) Pub Date : 2020-12-21 Weibin Xiao; Zhirong Deng; Chongfa Lai; Haoyang Lu; Mutu Huang; Yuguan Wen; Lei Shi
Abstract l-THP is mainly metabolized by CYP450 enzymes. This study was to investigate the possible effect of co-administered CYP inhibitors on the pharmacokinetics of l-tetrahydropalmatine (l-THP) and its metabolites in rats. An established LC-MS/MS method has been applied for evaluation of drug-drug interaction between l-THP and CYP inhibitors. Following the administration of CYP inhibitors, a single
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Comparative HPLC-MS/MS-based pharmacokinetic studies of multiple diterpenoid alkaloids following the administration of Zhenwu Tang and Radix Aconiti Lateralis Praeparata extracts to rats Xenobiotica (IF 1.902) Pub Date : 2020-12-17 Yanhao Liu; Hua Sun; Chao Li; Zhicheng Pu; Zijing Wu; Maodi Xu; Xianghong Li; Yuanxiang Zhang; Hongjin Li; Jian Dong; Runlei Bi; Haitang Xie; Dahu Liang
Abstracts Zhenwu Tang (ZWT) is a traditional Chinese medicine that is primarily composed of Radix Aconiti Lateralis Praeparata (FZ) and diterpenoid alkaloids are believed to be the pharmacologically active compounds of ZWT. In this study, the pharmacokinetic profiles of hypaconitine, mesaconitine, aconitine, benzoylmesaconitine, benzoylaconitine, and benzoylhypacoitine were assessed in rats following
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Tolerability, safety, pharmacokinetics and pharmacodynamics of SHR0534, a potent G protein-coupled receptor 40 (GPR40) agonist, at single- and multiple-ascending oral doses in healthy chinese subjects Xenobiotica (IF 1.902) Pub Date : 2020-12-17 Yuqing Zhao; Lijun Xie; Ning Ou; Jie Wu; Hongwen Zhang; Sufeng Zhou; Yun Liu; Juan Chen; Lu Wang; Li-bin Wang; Jingjing Wang; Feng Shao
Abstract SHR0534 is being developed for type 2 diabetes mellitus. Herein the tolerability, safety, pharmacokinetics and pharmacodynamics of SHR0534 in healthy Chinese subjects were assessed in a phase I, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study. Forty subjects were randomized 4:1 to receive SHR0534 at the dose of 10, 25, 50 or 100 mg, or placebo, and another
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Tissue and interspecies comparison of catechol-O-methyltransferase mediated catalysis of 6-O-methylation of esculetin to scopoletin and its inhibition by entacapone and tolcapone Xenobiotica (IF 1.902) Pub Date : 2020-12-08 Aaro Jalkanen; Veera Lassheikki; Tommi Torsti; Elham Gharib; Marko Lehtonen; Risto O. Juvonen
Abstract Catechol-O-methyltransferase (COMT) methylates both endogenous and exogenous catechol compounds to inactive and safe metabolites. We first optimized conditions for a convenient and sensitive continuous fluorescence-based 6-O-methylation assay of esculetin, which we used for investigating the COMT activity in human, mouse, rat, dog, rabbit, and sheep liver cytosols and microsomes and in ten
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Absorption, distribution, metabolism, and excretion of three [14C]PBDE congeners in laying hens and transfer to eggs Xenobiotica (IF 1.902) Pub Date : 2020-12-08 Heldur Hakk; Colleen Pfaff; Sara J Lupton; Anuradha Singh
Abstract Polybrominated diphenyl ethers (PBDEs) levels in environmental matrices have generally declined following their phaseout as flame retardants. The objective of this study was to determine the absorption, distribution, metabolism, and excretion of three persistent PBDEs in laying hens and their transfer into eggs. Laying hens (n = 4 per congener) received a single oral dose of BDE-99, -153,
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Rapid Determination of the Pharmacokinetics and Metabolic Fate of Gefitinib in the Mouse Using a Combination of UPLC/MS/MS, UPLC/QToF/MS and Ion Mobility (IM)-Enabled UPLC/QToF/MS Xenobiotica (IF 1.902) Pub Date : 2020-12-07 Billy J Molloy; Adam King; Lauren Mullin; Lee A. Gethings; Robert Riley; Robert S Plumb; Ian D Wilson
Abstract The metabolism and pharmacokinetics of gefitinib (Iressa®, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholino-propoxy)quinazolin-4-amine), a selective thymidylate kinase inhibitor for the epidermal growth factor receptor (EGFR) was studied after IV and PO administration to male C57BL6 mice at 10 and 50 mg/kg respectively. The pharmacokinetics and metabolism of gefitinib were investigated
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Inhibitory effect of sixteen pharmaceutical excipients on six major organic cation and anion uptake transporters. Xenobiotica (IF 1.902) Pub Date : 2020-10-12 Ruicong Ma,Gentao Li,Xue Wang,Yajuan Bi,Youcai Zhang
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 16 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
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Comprehensive Identification, Fragmentation Pattern and Metabolic Pathways of Gefitinib Metabolites via UHPLC-Q-TOF-MS/MS: In Vivo Study of Rat Plasma, Urine, Bile and Feces Xenobiotica (IF 1.902) Pub Date : 2020-12-03 Xun Gao; Yue Zhang; Tiantian Feng; Lei Cao; Wenjing Wu; Kunming Qin
Abstract Gefitinib, the first approved inhibitor for oral epidermal growth factor receptor (EGFR), has been proved to be effective in non-small cell lung cancer with EGFR mutation. However, there are many metabolites of gefitinib that have not been identified in vivo. This study aims to identify the metabolites of gefitinib and its metabolic pathways in rats using ultra-high-performance liquid chromatography
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Effects of Breviscapine and C3435T MDR1 gene polymorphism on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate, in healthy volunteers Xenobiotica (IF 1.902) Pub Date : 2020-12-01 Zhao Yingying; Miao Zhimin; Jiang Mingzhao; Xuan Zhou; Yong Lai
Abstract Breviscapine is usually used for long-term use in patients with cardiovascular diseases such as coronary heart disease, angina pectoris, and cerebral thrombosis. It is possible to combine it with P-glycoprotein (P-gp) substrates in clinic. At present, little is known about whether the simultaneous use of BRE affects the disposal of P-gp substrates. The aim of this study was to evaluate the
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A Comprehensive Profiling and Identification of Liquiritin Metabolites in Rats using Ultra-high-performance Liquid Chromatography Coupled with Linear Ion Trap–Orbitrap Mass Spectrometer Xenobiotica (IF 1.902) Pub Date : 2020-11-21 Shan Jiang; Shaoping Wang; Pingping Dong; Lei Shi; Qiyan Li; Xia Wei; Peng Gao; Jiayu Zhang
Abstract Liquiritin (LQ), a main component of liquorice, exerts various biological activities. However, insufficient attentions have been paid to the metabolism study on this natural compound until now. Our present study was conducted to investigate the LQ metabolites in rats urine, faeces and plasma using UHPLC-LTQ-Orbitrap mass spectrometer in both positive and negative ion modes. Meanwhile, post-acquisition
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Pharmacokinetic changes of clozapine and norclozapine in a rat model of non-alcoholic fatty liver disease induced by orotic acid Xenobiotica (IF 1.902) Pub Date : 2020-11-13 Zhengri Li; Song Hee Lee; Hee Jin Jeong; Hee Eun Kang
Abstract Impaired in vitro oxidation of clozapine has been reported in steatotic rat liver due to downregulation of cytochrome P450 (CYP) 1A. Pharmacokinetic changes of clozapine and its major metabolite, norclozapine, were evaluated in a rat model of non-alcoholic fatty liver disease (NAFLD) induced by orotic acid. Significantly slower in vitro CLint for formation of norclozapine from clozapine was
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Plasma and Hepatic Concentrations of Acetaminophen and Its Primary Conjugates after Oral Administrations Determined in Experimental Animals and Humans and Extrapolated by Pharmacokinetic Modeling Xenobiotica (IF 1.902) Pub Date : 2020-11-12 Akiko Toda; Makiko Shimizu; Shotaro Uehara; Tatsuro Sasaki; Tomonori Miura; Masayuki Mogi; Masahiro Utoh; Hiroshi Suemizu; Hiroshi Yamazaki
Abstract Plasma concentrations of acetaminophen, its glucuronide and sulfate conjugates, and cysteinyl acetaminophen were experimentally determined after oral administrations of 10 mg/kg in humanized-liver mice, control mice, rats, common marmosets, cynomolgus monkeys, and minipigs; the results were compared with reported human pharmacokinetic data. Among the animals tested, only rats predominantly
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Pharmacokinetics, tissue distribution and excretion of a novel long-acting human insulin analogue -recombinant insulin LysArg in rats Xenobiotica (IF 1.902) Pub Date : 2020-11-05 Tao Cui; Yazhuo Li; Zihong Wei; Xingyan Zhang; Wei Li; Wei Zhou; Jiangjie Lu; Jing Li; Xiulin Yi; Yong Zeng; Changxiao Liu; Fengying Yan
Abstract As a novel long-acting recombinant human insulin analogue, it is necessary to carry out the preclinical research for insulin LysArg. The purpose of this study was to characterize the pharmacokinetic, tissue distribution and excretion of insulin LysArg and provide a reference for its development. Three methods were used to measure the content of insulin LysArg in biological samples after a
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Human Mass Balance, Metabolism, and Cytochrome P450 Phenotyping of Lusutrombopag Xenobiotica (IF 1.902) Pub Date : 2020-10-30 Tomoyuki Kawachi; Mizuki Ninomiya; Takayuki Katsube; Toshihiro Wajima; Takushi Kanazu
Abstract The human mass balance of lusutrombopag, an orally bioavailable thrombopoietin (TPO) receptor agonist, was characterized in seven healthy male subjects after a single oral dose of [14C]-lusutrombopag (2 mg, 100 μCi) in solution. Lusutrombopag was the main component in plasma, accounting for 56% of plasma radioactivity AUC0-∞. In plasma, the half-life of radioactivity (70.7 h) was longer than
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Oral antibiotics used in the treatment of chronic rhinosinusitis have limited penetration into the sinonasal mucosa: a randomized trial. Xenobiotica (IF 1.902) Pub Date : 2020-09-04 Joey Siu,Lilian Klingler,Yi Wang,Cheung-Tak Hung,Soo Hee Jeong,Susan Smith,Malcolm Drummond Tingle,Brett Wagner Mackenzie,Kristi Biswas,Richard George Douglas
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
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In vitro study on the effect of ophiopogonin D on the activity of cytochrome P450 enzymes Xenobiotica (IF 1.902) Pub Date : 2020-10-29 Xiaofei Ji; Baodong Ding; Xiaoyou Wu; Fengyi Liu; Fengqi Yang
Abstract Ophiopogonin D is a commonly used herb in cardiology for its cardioprotective effect. It is necessary to investigate the effect of ophiopogonin D on the activity of cytochrome P450 enzymes (CYP450s) to provide more guidance for the clinical application of ophiopogonin D. Eight isoforms of CYP450s, including CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 were incubated with 100 μM ophiopogonin
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In vitro metabolism assessment of thiacloprid in rainbow trout and rat by LC-UV and high resolution-mass spectrometry Xenobiotica (IF 1.902) Pub Date : 2020-10-21 Jose Serrano; Richard C. Kolanczyk; Brett R. Blackwell; Barbara R. Sheedy; Mark A. Tapper
Abstract Thiacloprid (THI) is a widely used neonicotinoid insecticide where concerns have been raised regarding low absorption by crops, substantial distribution in surrounding areas, and potential adverse effects to terrestrial and aquatic organisms. Prior to this study, there was very limited information addressing the ex vivo (precision-cut liver slices) metabolism of THI by fish species and the
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Assessment of the in vitro cytochrome P450 (CYP) inhibition potential of Nafithromycin, a next generation lactone ketolide antibiotic Xenobiotica (IF 1.902) Pub Date : 2020-10-20 Rajesh P. Chavan; Vineet S. Zope; Nilesh N. Chavan; Kiran Patil; Ravindra D. Yeole; Sachin B. Bhagwat; Mahesh V. Patel
Abstract Nafithromycin is a next generation lactone ketolide antibiotic slated to enter phase III clinical development in India for the treatment of CABP as a shorter 800mg-OD X3 day therapeutic regimen. Nafithromycin exhibits potent activity against MDR Streptococcus pneumoniae including erythromycin and telithromycin-resistant resistant strains. Older macrolides/ketolides are reported to be potent
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Comparative toxicokinetics of bisphenol S and bisphenol AF in male rats and mice following repeated exposure via feed Xenobiotica (IF 1.902) Pub Date : 2020-10-06 Suramya Waidyanatha; Sherry R. Black; Claire R. Croutch; Bradley J. Collins; Melanie A. R. Silinski; Season Kerns; Vicki Sutherland; Veronica G. Robinson; Kristin Aillon; Reshan A. Fernando; Esra Mutlu; Timothy R. Fennell
Abstract We investigated the plasma toxicokinetic behavior of free (parent) and total (parent and conjugated forms) of bisphenol S (BPS) and bisphenol AF (BPAF) in plasma of adult male rats and mice following exposure via feed for 7 days to BPS (338, 1125, and 3375 ppm) or BPAF (338, 1125, and 3750 ppm). In rats, the exposure concentration-normalized maximum concentration [Cmax/D (ng/mL)/(ppm)] and
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Optimization of hydroxychloroquine dosing scheme based on COVID-19 patients' characteristics: a review of the literature and simulations. Xenobiotica (IF 1.902) Pub Date : 2020-09-30 Eleni Karatza,George Ismailos,Markos Marangos,Vangelis Karalis
Abstract During the recent COVID-19 outbreak hydroxychloroquine (HCQ) has been proposed as a safe and effective therapeutic option. However, a wide variety of dosing schemes has been applied in the clinical practice and tested in clinical studies. An extended literature survey was performed investigating the pharmacokinetics, the efficacy and safety of HCQ in COVID-19 treatment. Population pharmacokinetic
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Correction. Xenobiotica (IF 1.902) Pub Date : 2020-09-28
(2021). Correction. Xenobiotica: Vol. 51, No. 2, pp. 249-249.
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Enantioselective in vitro ADME, absolute oral bioavailability, and pharmacokinetics of (-)-lumefantrine and (+)-lumefantrine in mice. Xenobiotica (IF 1.902) Pub Date : 2020-09-23 Bhavesh Babulal Gabani,Abhishek Dixit,Vinay Kiran,Ram Murthi Bestha,Balaji Narayanan,Nuggehally R Srinivas,Ramesh Mullangi
Abstract Lumefantrine (LFN) is a chiral antimalarial 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
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Pharmacokinetic interaction between dronedarone and ticagrelor following oral administration in rats. Xenobiotica (IF 1.902) Pub Date : 2020-09-22 Dong Kyun Kim,Soo Yong Chung,Jae-Hwan Kwak,Min-Soo Kim,Christine E Staatz,Hye Suk Lee,In-Hwan Baek
Abstract Dronedarone and ticagrelor have high co-administration potential in patients with both acute coronary syndrome and atrial fibrillation. 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;
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Evaluation of covalent binding of flutamide and its risk assessment using 19F-NMR. Xenobiotica (IF 1.902) Pub Date : 2020-09-22 Nobuyuki Kakutani,Takahiro Iwai,Yasushi Ohno,Satoru Kobayashi,Yukihiro Nomura
Abstract The formation of reactive metabolites (RMs) is a problem in drug development that sometimes results in severe hepatotoxicity. As detecting RMs themselves is difficult, a covalent binding assay using expensive radiolabelled tracers is usually performed for candidate selection. This study aimed to provide a practical approach toward the risk assessment of hepatotoxicity induced by covalent binding
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Metabolism and disposition in rats, dogs, and humans of erdafitinib, an orally administered potent pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. Xenobiotica (IF 1.902) Pub Date : 2020-09-20 Ellen Scheers,Carine Borgmans,Chi Keung,Hilde Bohets,Inneke Wynant,Italo Poggesi,Filip Cuyckens,Laurent Leclercq,Rao N V S Mamidi
Abstract 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 (T max: animals, 1 h; humans
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Population pharmacokinetics of mycophenolic acid in pediatric patients with juvenile dermatomyositis and optimization of limited sampling strategy. Xenobiotica (IF 1.902) Pub Date : 2020-09-16 Guangfei Wang,Qiaofeng Ye,Yidie Huang,Jinmiao Lu,Hong Xu,Zhiping Li
Abstract Juvenile dermatomyositis (JDM) is a rare systemic autoimmune disease specifically affecting children. Mycophenolate mofetil (MMF) is an immunosuppressant used to treat JDM. Mycophenolic acid (MPA) is an active metabolite of MMF. This study aimed to develop a population pharmacokinetic (PPK) model of MPA in children with JDM and optimize the limited sampling strategy (LSS). Fifteen JDM patients
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Inhibition of CYP3A4 and CYP3A5 expression by scutellarin is not mediated via the regulation of hsa-miR-27a, 27b, 148a, 298 and 451a levels. Xenobiotica (IF 1.902) Pub Date : 2020-08-12 Weiyao Ding,Change Cao,Yangyang Gao,Xuan Zhou,Yong Lai
1. Scutellarin is a flavonoid glycoside widely used in the treatment of cardio-cerebrovascular diseases in China. In this study, we investigated the effect of scutellarin on cytochrome P450 3A4 (CYP3A4) and CYP3A5 expression. Furthermore, we studied the expression of hsa-miR-27a, hsa-miR-27b, hsa-miR-148a, hsa-miR-298 and hsa-miR-451a in humans to determine whether scutellarin regulated CYP3A4 and
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Numerical analysis of time-dependent inhibition kinetics: comparison between rat liver microsomes and rat hepatocyte data for mechanistic model fitting. Xenobiotica (IF 1.902) Pub Date : 2020-08-24 Chuong Pham,Swati Nagar,Ken Korzekwa
Time-dependent inhibition (TDI) may confound drug interaction predictions. Recently, models were generated for an array of TDI kinetic schemes using numerical analysis of microsomal assays. Additionally, a distinct terminal inactivation step was identified for certain mechanism based inhibitors (MBI) following reversible metabolite intermediate complex (MIC) formation. Longer hepatocyte incubations
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Metabolism study of hesperetin and hesperidin in rats by UHPLC-LTQ-Orbitrap MS n. Xenobiotica (IF 1.902) Pub Date : 2020-08-12 Qishu Jiao,Lulu Xu,Lijuan Jiang,Yanyan Jiang,Jiayu Zhang,Bin Liu
Hesperidin (HPD) and hesperetin (HPT), as a kind of flavonone compounds, are abundant in citrus fruits with various pharmacological effects. HPD and HPT are not always consistent in some biological activities, even if they have the same skeletal structure. The aim of this study was to screen and identify HPT and HPD metabolites in rats using UHPLC-LTQ-Orbitrap MS n , compare the possible metabolism
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Bidirectional regulation of genistein on the proliferation and differentiation of C2C12 myoblasts. Xenobiotica (IF 1.902) Pub Date : 2020-08-24 Mailin Gan,Dongli Yang,Yuan Fan,Jingjing Du,Linyuan Shen,Qiang Li,Yanzhi Jiang,Guoqing Tang,Mingzhou Li,Jinyong Wang,Xuewei Li,Shunhua Zhang,Li Zhu
Genistein is a widely studied phytoestrogen. The effects of genistein on myoblasts were reported long ago, but the conclusions are controversial. In this study, we evaluated the effects of different concentrations of genistein on C2C12 myoblasts. Genistein treatment promoted myoblast proliferation in a dose-dependent manner in the concentration range of 0–2 µM/L, reaching its maximum effect at 2 µM/L
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In vitro inhibition and induction of human liver cytochrome P450 enzymes by a novel anti-fibrotic drug fluorofenidone. Xenobiotica (IF 1.902) Pub Date : 2020-09-08 Linling Li,Xi Luo,Zeneng Cheng
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
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MRP4 is responsible for the efflux transport of mycophenolic acid β-d glucuronide (MPAG) from hepatocytes to blood. Xenobiotica (IF 1.902) Pub Date : 2020-09-06 Joseph Berthier,Mehdi Benmameri,François-Ludovic Sauvage,Gabin Fabre,Benjamin Chantemargue,Hélène Arnion,Pierre Marquet,Patrick Trouillas,Nicolas Picard,Franck Saint-Marcoux
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 transporters is still fragmented. The aim of the present study was to explore these interactions
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Main contribution of UGT1A1 and CYP2C9 in the metabolism of UR-1102, a novel agent for the treatment of gout. Xenobiotica (IF 1.902) Pub Date : 2020-08-30 Mizuki Yamane,Fumihiko Igarashi,Tsuyoshi Yamauchi,Toshito Nakagawa
Abstract UR-1102, a novel uricosuric 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
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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. Xenobiotica (IF 1.902) Pub Date : 2020-08-26 Roger J Price,Mary P Scott,Carina Cantrill,Larry G Higgins,Marjory Moreau,Miyoung Yoon,Harvey J Clewell,Moire R Creek,Thomas G Osimitz,J Brian Houston,Brian G Lake
Abstract The kinetics of metabolism of deltamethrin (DLM) and cis- and trans-permethrin (CPM and TPM) was studied in male Sprague-Dawley rat and human liver microsomes. DLM metabolism kinetics was also studied in isolated rat hepatocytes, liver microsomes and cytosol. Apparent intrinsic clearance (CLint) values for the metabolism of DLM, CPM and TPM by cytochrome P450 (CYP) and carboxylesterase (CES)
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Characterization of plasma protein binding in two mouse models of humanized liver, PXB mouse and humanized TK-NOG mouse Xenobiotica (IF 1.902) Pub Date : 2020-08-25 Maki Miyamoto; Yohei Kosugi; Shinji Iwasaki; Ikumi Chisaki; Sayaka Nakagawa; Nobuyuki Amano; Hideki Hirabayashi
Abstract The unbound fractions in plasma (f up) in two mouse models of humanized liver mice, PXB and humanized TK-NOG mice, were compared with human f up values using equilibrium dialysis method. A good relationship between f up values obtained from PXB mice and humans was observed; the f up of 34/39 compounds (87.2%) in PXB mice were within 3-fold of human f up. In contrast, a weak correlation was
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The influence of multiple oral administration on the pharmacokinetics and distribution profile of dalcetrapib in rats. Xenobiotica (IF 1.902) Pub Date : 2020-08-20 Hiroaki Takubo,Tomohiro Ishikawa,Toshio Taniguchi,Kazunori Iwanaga,Yukihiro Nomura
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
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Genetic variants of UDP-glucuronosyltransferases 1A1, 1A6, and 1A9 in cynomolgus and rhesus macaques. Xenobiotica (IF 1.902) Pub Date : 2020-08-19 Yasuhiro Uno,Takahiro Mikami,Yasuko Tsukazaki,Yasuharu Nakanishi,Norie Murayama,Shinichi Ikushiro,Hideshi Tsusaki,Hiroshi Yamazaki
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
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The use of inactivated brain homogenate to determine the in vitro fraction unbound in brain for unstable compounds. Xenobiotica (IF 1.902) Pub Date : 2020-06-05 Ramakrishna Nirogi,Parusharamulu Molgara,Gopinadh Bhyrapuneni,Arunkumar Manoharan,Nagasurya Prakash Padala,Veera Raghava Chowdary Palacharla
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
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Evaluation of the changes in exposure to thiol compounds in chronic kidney disease patients using the PBPK model. Xenobiotica (IF 1.902) Pub Date : 2020-08-12 Hiroaki Takubo,Toshio Taniguchi,Kazunori Iwanaga,Yukihiro Nomura
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
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Characterization of plasma protein binding in two mouse models of humanized liver, PXB mouse and humanized TK-NOG mouse Xenobiotica (IF 1.902) Pub Date : 2020-08-11 Maki Miyamoto; Yohei Kosugi; Shinji Iwasaki; Ikumi Chisaki; Sayaka Nakagawa; Nobuyuki Amano; Hideki Hirabayashi
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
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Comparative assessment for rat strain differences in metabolic profiles of 14 drugs in Wistar Han and Sprague Dawley hepatocytes. Xenobiotica (IF 1.902) Pub Date : 2020-07-27 Wei Wang,Mulder Teresa,Jingwei Cai,Chenghong Zhang,Susan Wong,Zhengyin Yan,S Cyrus Khojasteh,Donglu Zhang
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
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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. Xenobiotica (IF 1.902) Pub Date : 2020-07-27 Wei Qin,Xiaoxue Wang,Wenqian Chen,Wenwen Du,Dan Zhang,Xianglin Zhang,Pengmei Li
Abstract 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
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Plasma protein binding, metabolism, reaction phenotyping and toxicokinetic studies of fenarimol after oral and intravenous administration in rats. Xenobiotica (IF 1.902) Pub Date : 2020-07-27 Kajal Karsauliya,Ashish Kumar Sonker,Manisha Bhateria,Isha Taneja,Anshuman Srivastava,Manu Sharma,Sheelendra Pratap Singh
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
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Nonadditivity in human microsomal drug metabolism revealed in a study with coumarin 152, a polyspecific cytochrome P450 substrate. Xenobiotica (IF 1.902) Pub Date : 2020-07-26 Bikash Dangi,Nadezhda Y Davydova,Nikita E Vavilov,Victor G Zgoda,Dmitri R Davydov
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
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