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Drug Metabolism and Disposition: the Biological Fate of Chemicals

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https://www.readbyqxmd.com/read/30630815/clopidogrel-and-gemfibrozil-strongly-inhibit-the-cyp2c8-dependent-formation-of-3-hydroxydesloratadine-and-increase-desloratadine-exposure-in-humans
#1
Matti K Itkonen, Aleksi Tornio, Mikko Neuvonen, Pertti J Neuvonen, Mikko Niemi, Janne T Backman
A recent in vitro study suggested that CYP2C8 is essential in the metabolism of desloratadine, a H1 receptor antagonist. If the proposed biotransformation mechanism takes place in vivo in humans, desloratadine could serve as a selective CYP2C8 probe substrate in drug-drug interaction studies. Glucuronide metabolites of clopidogrel and gemfibrozil act as time-dependent inhibitors of CYP2C8, but they have not been compared clinically. We conducted a randomized cross-over study in eleven healthy subjects to characterize the involvement of CYP2C8 in desloratadine metabolism and to compare the CYP2C8 inhibitory strength of clopidogrel (300 mg, and 75 mg on 2 following days) with that of gemfibrozil (600 mg b...
January 10, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30622164/a-comparison-of-total-and-plasma-membrane-abundance-of-transporters-in-suspended-plated-sandwich-cultured-human-hepatocytes-vs-human-liver-tissue-using-quantitative-targeted-proteomics-and-cell-surface-biotinylation
#2
Vineet Kumar, Laurent Salphati, Cornelis E C A Hop, Guangqing Xiao, Yurong Lai, Anita Mathias, Xiaoyan Chu, W Griffith Humphreys, Mingxiang Liao, Scott Heyward, Jashvant D Unadkat
Suspended (SH), plated (PH) and sandwich-cultured hepatocytes (SCH) are commonly used models to predict in vivo transporter-mediated hepatic uptake (SH or PH) or biliary (SCH) clearance of drugs. When doing so, the total and plasma membrane abundance (PMA) of the transporter is assumed not to differ between hepatocytes and liver tissue (LT). This assumption has never been tested. Here, we tested this assumption by measuring the total and PMA of transporters in human hepatocyte models vs. LT (total only) from which they were isolated...
January 8, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30622163/effect-of-osmolality-on-the-pharmacokinetic-interaction-between-apple-juice-and-atenolol-in-rats
#3
Yuta Funai, Yoshiyuki Shirasaka, Marika Ishihara, Miyuki Takemura, Kazuki Ichijo, Hisanao Kishimoto, Katsuhisa Inoue
In a recent clinical study, it was reported that the ingestion of apple juice (AJ) markedly reduced the plasma concentration of atenolol. However, our in vitro study showed that atenolol may not be a substrate of OATP2B1, so this AJ-atenolol interaction cannot be explained by inhibition of OATP2B1. On the other hand, we more recently showed that the solution osmolality influences gastrointestinal (GI) water volume, and this may indirectly affect intestinal drug absorption. In this study, we examined whether the osmolality-dependence of water dynamics can account for AJ-atenolol interactions by evaluating the GI water volume and the atenolol aborption in the presence of AJ in rats...
January 8, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30610004/use-of-segregated-hepatocyte-scaling-factors-and-cross-species-relationship-to-resolve-clearance-dependency-in-prediction-of-human-hepatic-clearance
#4
David Hallifax, James Brian Houston
Human and rat hepatocytes have a strong tendency to underpredict hepatic intrinsic clearance (CLint) and the extent of under prediction increases with increasing observed CLint (Wood et al., 2017, Drug Metab and Dispos 45: 1178-1188). In the present study, application of the log average rat hepatocyte-rat in vivo empirical scaling factor (ESF) of 4.2 to human hepatocyte prediction (from the Wood et al database) successfully removed bias but did not improve precision. An analogous method, using individual drug rat ESFs only achieved marginal improvement in accuracy but not precision...
January 4, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30606729/continuum-of-host-gut-microbial-co-metabolism-host-cyp3a4-3a7-are-responsible-for-tertiary-oxidations-of-deoxycholate-species
#5
Jian Zhang, Ling-Zhi Gao, Yu-Jie Chen, Ping-Ping Zhu, Shan-Shan Yin, Ming-Ming Su, Yan Ni, Jia Miao, Wen-Lin Wu, Hong Chen, Kim L R Brouwer, Chang-Xiao Liu, Liang Xu, Wei Jia, Ke Lan
The gut microbiota modifies endogenous primary bile acids (BAs) to produce exogenous secondary BAs, which may be further metabolized by cytochrome P450 enzymes (CYPs). Our primary aim was to examine how the host adapts to the stress of microbe-derived secondary BAs by CYPs-mediated oxidative modifications on the steroid nucleus. Five unconjugated tri-hydroxyl BAs that were structurally and/or biologically associated with deoxycholate (DCA) were determined in human biological samples by LC-MS/MS in combination with enzyme-digestion techniques...
January 3, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30606728/the-mbnl-celf-splicing-factors-regulate-cytosolic-sulfotransferase-4a1-protein-expression-during-cell-differentiation
#6
Misgana Idris, Neville J Butcher, Rodney F Minchin
Sulfotransferase 4A1 (SULT4A1) is a sulfotransferase-like protein that is highly conserved between species. In human tissues, there are 2 transcripts, one that produces a full length protein and one that produces an unstable truncated protein. The second transcript, which includes a pseudo-exon between exons 6 and 7 (6p), is widely expressed while the first is more restricted. Differentiation of neuronal cells results in the removal of the pseudo-exon and subsequent SULT4A1 protein expression. Recent studies with SULT4A1 knockout mice showed that the protein is essential for normal development and that its absence leads to a severe neurological phenotype...
January 3, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30602435/breast-cancer-resistance-protein-and-multidrug-resistance-protein-2-determine-the-disposition-of-esculetin-7-o-glucuronide-and-4-methylesculetin-7-o-glucuronide
#7
Yuhuan Li, Wenjie Song, Xiaojun Ou, Guangkuo Luo, Yushan Xie, Rongjin Sun, Ying Wang, Xiaoxiao Qi, Ming Hu, Zhongqiu Liu, Lijun Zhu
Esculetin-7-O-glucuronide (ET-G) and 4-Methylesculetin-7-O-glucuronide (4-ME-G) are the main glucuronide of esculetin (ET) and 4-methylesculetin (4-ME), respectively. The disposition mediated by efflux transporters for glucuronide has significant influence on the pharmacokinetic profile and efficacy of bioactive compounds. In the current study, transporter gene knockout mice and Caco-2 cells were used to explore the effects of breast cancer resistance protein (BCRP) and multidrug resistance protein 2 (MRP2) on the disposition of ET-G and 4-ME-G...
January 2, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30598508/commensal-gut-bacteria-convert-the-immunosuppressant-tacrolimus-to-less-potent-metabolites
#8
Yukuang Guo, Camila Manoel Crnkovic, Kyoung-Jae Won, Xiaotong Yang, John Richard Lee, Jimmy Orjala, Hyunwoo Lee, Hyunyoung Jeong
Tacrolimus exhibits low and variable drug exposure after oral dosing, but the contributing factors remain unclear. Based on our recent report showing a positive correlation between fecal abundance of Faecalibacterium prausnitzii and oral tacrolimus dose in kidney transplant patients, we tested whether F. prausnitzii and other gut abundant bacteria are capable of metabolizing tacrolimus. Incubation of F. prausnitzii with tacrolimus led to production of two compounds (the major one named M1), which was not observed upon tacrolimus incubation with hepatic microsomes...
December 31, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30593545/in-silico-prediction-of-the-absorption-and-disposition-of-cefadroxil-in-humans-using-an-intestinal-permeability-method-scaled-from-humanized-pept1-mice
#9
Yongjun Hu, David E Smith
It is difficult to predict the pharmacokinetics and plasma concentration-time profiles of new chemical entities in humans based on animal data. Some pharmacokinetic parameters, such as clearance and volume of distribution, can be scaled allometrically from rodents, mammals and non-human primates with good success. However, it is far more challenging to predict the oral pharmacokinetics of experimental drug candidates. In the present study, we used in situ estimates of intestinal permeability, obtained in silico and from rat, wildtype (WT) and humanized PepT1 (huPepT1) mice, to predict the systemic exposure of cefadroxil, an orally administered model compound, under a variety of conditions...
December 28, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30593544/hepatic-oatp-mediated-clearance-in-the-beagle-dog-assessing-in-vitro-in-vivo-relationships-and-applying-cross-species-empirical-scaling-factors-to-improve-prediction-of-human-clearance
#10
Norikazu Matsunaga, Ayse Ufuk, Bridget L Morse, David W Bedwell, Jingqi Bao, Michael A Mohutsky, Kathleen M Hillgren, Stephen D Hall, James Brian Houston, Aleksandra Galetin
In the present study the beagle dog was evaluated as a preclinical model to investigate organic anion transporting polypeptide (OATP)-mediated hepatic clearance. In vitro studies were performed with nine OATP substrates in three lots of plated male dog hepatocytes +/- OATP inhibitor cocktail to determine total uptake (CLuptake ), total and unbound cell-to-medium concentration ratio (Kpuu ). In vivo intrinsic hepatic clearances (CLint,H ) were determined following intravenous drug administration (0.1 mg/kg) in male beagle dogs...
December 28, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30593543/regulation-of-hepatic-long-non-coding-rnas-by-pxr-and-car-agonists-in-mouse-liver
#11
Joseph L Dempsey, Julia Yue Cui
Altered expression of lncRNAs by environmental chemicals modulates the expression of xenobiotic biotransformation related genes and may serve as therapeutic targets and novel biomarkers of exposure. The pregnane X receptor (PXR/NR1I2) is a critical xenobiotic-sensing nuclear receptor that regulates the expression of many drug-processing genes, and it has similar target gene profiles and DNA binding motifs with another xenobiotic-sensing nuclear receptor, namely constitutive andronstrane receptor (CAR/Nr1i3)...
December 28, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30578276/a-recombinant-humanized-anti-cocaine-monoclonal-antibody-alters-the-urinary-clearance-of-cocaine-and-its-metabolites-in-rats
#12
Jordan Marckel, Hanna Wetzel, Sihame Amlal, Hassane Amlal, Andrew Norman
A recombinant humanized anti-cocaine monoclonal antibody, (h2E2), has shown potential in the preclinical phases for the treatment of cocaine abuse. The standard tests for cocaine usage are the detection of benzoylecgonine (BE) and cocaine in the urine. This includes workplace drug screens as well as in clinical trials for potential treatments of cocaine abuse. By sequestering cocaine into the plasma compartment, h2E2 prevents cocaine from entering the brain. Due to the altered disposition of cocaine in the presence of h2E2, we investigated the effects of h2E2 on cocaine and metabolite levels in the urine of rats to clarify the use of BE as an endpoint measurement for effectiveness in the future clinical trials...
December 21, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30573465/suppression-of-hepatic-cyp3a4-expression-and-activity-by-3-methylcholanthrene-in-humanized-pxr-car-cyp3a4-3a7-mice
#13
Michael Crosby, David S Riddick
Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that activate the aryl hydrocarbon receptor, thereby triggering a range of biological responses, exemplified by the induction of cytochrome P450 1A1 ( CYP1A1 ). PAHs can also regulate the expression of members of the CYP3A subfamily, with reports of mainly suppressive effects on mouse hepatic Cyp3a11 expression but, paradoxically, both inductive and suppressive effects on human hepatic CYP3A4 expression. Understanding the regulation of CYP3A4 expression by PAHs is important because of the widespread exposure of humans to these chemicals and the central role of the CYP3A4 enzyme in the metabolism of clinically important drugs and endogenous substances...
December 20, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30567881/kinetics-of-cyclophosphamide-metabolism-in-human-dog-cat-and-mouse-and-relationship-to-cytotoxic-activity-and-pharmacokinetics
#14
Dominique A Ramirez, Keagan P Collins, Allister E Aradi, Katherine A Conger, Daniel L Gustafson
Cyclophosphamide (CP), a prodrug that is enzymatically converted to the cytotoxic 4-hydroxycyclophosphamide (4OHCP) by hepatic enzymes, is commonly used in both human and veterinary medicine to treat cancers and modulate the immune system. The metabolism of CP in humans, dogs, cats, and mice was investigated with liver microsomes and apparent KM , Vmax , and intrinsic clearance (Vmax /KM ,) parameters were estimated. The inter- and intra-species variation in kinetics was vast. Dog microsomes were, on average, 55-fold more efficient than human microsomes, 2...
December 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30567880/characterization-of-anacetrapib-distribution-into-the-lipid-droplet-of-adipose-tissue-in-mice-and-human-cultured-adipocytes
#15
Douglas G Johns, Lauretta LeVoci, Mihajlo Krsmanovic, Min Lu, Georgy Hartmann, Suoyu Xu, Sheng-Ping Wang, Ying Chen, Thomas Bateman, Robert O Blaustein
Anacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP), associated with reduction in LDL-cholesterol and increase in HDL-cholesterol in hypercholesterolemic patients. Anacetrapib was not taken forward into filing/registration as a new drug for coronary artery disease, despite observation of a ~9% reduction in cardiovascular risk in a large phase III cardiovascular outcomes trial (REVEAL). Anacetrapib displayed no adverse effects throughout extensive preclinical safety evaluation, and no major safety signals were observed in clinical trials studying anacetrapib, including REVEAL...
December 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30567879/gas-phase-rearrangement-of-the-o-glucuronide-of-vildagliptin-forms-product-ion-fragments-suggesting-wrongly-an-n-glucuronide
#16
Andreas Fredenhagen, Jurgen Kuhnol, Matthias Kittelmann, Lukas Oberer
The O -glucuronide of vildagliptin, a dipeptidyl peptidase 4 inhibitor (DPP-4), is a major metabolite in monkey and a minor metabolite in humans, rats and dogs. Its product ion spectrum shows fragments that can be only explained by an N -glucuronide. Biotransformation utilizing rat liver yielded mg amounts of the O -glucuronide and its structure was assigned unambiguously by NMR. The MS/MS spectrum of this compound was investigated in detail utilizing MSn and accurate mass spectrometers and was identical to the animal metabolite...
December 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30567878/physiology-of-the-neonatal-gastrointestinal-system-relevant-to-the-disposition-of-orally-administered-medications
#17
April Neal-Kluever, Jeffrey Fisher, Lawrence Grylack, Satoko Kakiuchi-Kiyota, Wendy Halpern
A thorough knowledge of the newborn (birth to one month postpartum age) infant's gastrointestinal tract (GIT) is critical to the evaluation of the absorption, metabolism, distribution, and excretion (ADME) of orally administered drugs in this population. Developmental changes in the GIT during the newborn period are important for nutrient uptake as well as the disposition of orally administered medications. Some aspects of gastrointestinal function do not mature until driven by increased dietary complexity and nutritional demands later in the postnatal period...
December 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30567877/hepatic-enzymes-relevant-to-the-disposition-of-%C3%AE-9-tetrahydrocannabinol-thc-and-its-psychoactive-metabolite-11-oh-thc
#18
Gabriela I Patilea-Vrana, Olena Anoshchenko, Jashvant D Unadkat
Marijuana use by pregnant women is increasing. To predict developmental risk to the fetus/neonate from such use, in-utero fetal exposure to (-)-Δ9 -tetrahydrocannabinol (THC), the main psychoactive cannabinoid in marijuana and its active psychoactive metabolite, 11-OH-THC, needs to be determined. Since such measurement is not possible, physiologically-based pharmacokinetic (PBPK) modeling and simulation can provide an alternative method to estimate fetal exposure to cannabinoids. To do so, pharmacokinetic parameters for the disposition of THC and 11-OH-THC need to be elucidated...
December 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30541878/pharmacokinetics-metabolism-and-excretion-of-14c-esaxerenone-a-novel-mineralocorticoid-receptor-blocker-in-humans
#19
Makiko Yamada, Jeanne Mendell, Hideo Takakusa, Takako Shimizu, Osamu Ando
Esaxerenone (CS-3150) is a novel non-steroidal selective mineralocorticoid receptor blocker. The absorption, metabolism, distribution and excretion (ADME) of esaxerenone was assessed in in vitro studies and a clinical study of [14 C]esaxerenone (150 μCi/20 mg) administered orally to 6 healthy male subjects. Plasma concentrations of esaxerenone and metabolites M4, M11 and M1 were measured by LC-MS/MS methods. Recovery of radioactivity was 92.5% with 38.5% and 54.0% excreted in urine and feces, respectively...
December 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30541877/drug-and-chemical-glucosidation-by-control-supersomestm-and-membranes-from-spodoptera-frugiperda-sf-9-cells-implications-for-the-apparent-glucuronidation-of-xenobiotics-by-udp-glucuronosyltransferase-1a5
#20
Nuy Chau, Leyla Kaya, Benjamin C Lewis, Peter I Mackenzie, John O Miners
Accumulating evidence indicates that several human UDP-glucuronosyltransferase enzymes catalyze both glucuronidation and glucosidation reactions. Baculovirus-infected insect cells (Trichoplusia ni and Spodoptera frugiperda (Sf9)) are used widely for the expression of recombinant human UGT enzymes. Following the observation that control Supersomes (c-SUP) express a native enzyme capable of glucosidating morphine, we characterized the glucosidation of a series of aglycones with either a hydroxyl (aliphatic or phenolic), carboxylic acid or amine functional group by c-SUP and membranes from uninfected Sf9 cells...
December 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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