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Drug Metabolism and Disposition: the Biological Fate of Chemicals

Philip A Krieter, C Nora Chiang, Shwe Gyaw, Phil Skolnick, Rebekah Snyder
Naloxone, a mu opioid receptor antagonist, is administered intranasally to reverse an opioid overdose but its short half-life may necessitate another dose after only 1 hour. The addition of naltrexone, another µ receptor antagonist which has a reported half-life of approximately 4 hours after oral administration, may extend its effectiveness. In a Phase 1 pharmacokinetic study, healthy adults were administered IN naloxone and naltrexone separately and in combination. When administered together, the Cmax of naltrexone decreased 61% and AUC0-inf decreased 32% compared to when it was given separately; lower concentrations of naltrexone were observed as early as 5 minutes post-dose...
April 16, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Kaori Nozaki, Masataka Nakano, Chika Iwakami, Tatsuki Fukami, Miki Nakajima
A-to-I RNA editing, the most frequent type of RNA editing in mammals, is catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes. Recently, we found that there is a large interindividual variation in the expression of ADAR1 protein in the human livers. In this study, we investigated the possibility that A-to-I RNA editing may modulate the expression of cytochrome P450 (P450), causing interindividual variations in drug metabolism potencies. We found that knockdown of ADAR1 or ADAR2 in HepaRG cells resulted in the decreased expression of CYP2B6 and CYP2C8 mRNA and protein...
April 15, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Elizabeth Hausner, Susan A Elmore, Xi Yang
Metabolism in organs other than liver and kidneys may play a significant role in how a specific organ responds to chemicals. The heart has metabolic capability for energy production and homeostasis. This homeostatic machinery can also process xenobiotics. Cardiac metabolism includes expression of numerous organic anion transporters, organic cation transporters, organic carnitine (zwitterion) transporters, and ATP-binding cassette transporters. Expression and distribution of the transporters within the heart may vary depending upon age, disease, endocrine status, and various other factors...
April 9, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Chongzhuang Tang, Zhaoqiang Chen, Xiaojian Dai, Weiliang Zhu, Dafang Zhong, Xiaoyan Chen
Racemic proton pump inhibitors (PPIs) have been developed into pure enantiomers given superior pharmacokinetic profiles. However, after doses of single enantiomer PPIs, different degrees of chiral inversion were observed. We investigated the relationship between chiral inversion and reductive metabolism of PPIs, as well as the mechanism of reductive metabolism. In liver microsomes and Sprague-Dawley rats, PPI-thioethers were stereoselectively oxidized to (R)- and (S)-PPIs, indicating that thioethers could be the intermediates of chiral inversion...
April 8, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Sayaka Deguchi, Tomoki Yamashita, Keisuke Igai, Kazuo Harada, Yukiko Toba, Kazumasa Hirata, Kazuo Takayama, Hiroyuki Mizuguchi
Cytochrome P450 family 2 subfamily C member 19 (CYP2C19), in liver, plays important roles in terms of drug metabolism. It is known that CYP2C19 poor metabolizers (PMs) lack CYP2C19 metabolic capacity. Thus, unexpected drug-induced liver injury or decrease of drug efficacy would be caused in CYP2C19 substrate-treated CYP2C19 PMs. However, it is difficult to evaluate the safety and effectiveness of drugs and candidate compounds for CYP2C19 PMs because there is currently no model for this phenotype. Here, using human iPS cells and our highly efficient genome editing and hepatocyte differentiation technologies, we generated CYP2C19-knockout human iPS cell-derived hepatocyte-like cells (CYP2C19-KO HLCs) as a novel CYP2C19 PM model for drug development and research...
April 8, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Sarah M Glass, Sabrina M Leddy, Michael C Orwin, Garret P Miller, Kyle A Furge, Laura Lowe Furge
Rolapitant (Varubi®) is a high affinity NK1 receptor antagonist that was approved in September 2015 as a treatment for nausea and vomiting caused by chemotherapy. In vivo rolapitant moderately inhibits CYP2D6 for at least seven days after one 180 mg dose. Due to the long inhibition time, we investigated rolapitant as a possible mechanism-based inactivator of CYP2D6. Rolapitant docked in the active site of CYP2D6 and displayed type I binding to CYP2D6 with Ks of 1.2 ± 0.4 µM. However, in NADPH-, time-, and concentration-dependent assays of CYP2D6 activity, no evidence for mechanism-based inactivation and no metabolites of rolapitant were observed...
April 5, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Philippe B Pierrillas, Emilie Henin, Kathryn Ball, Julien Ogier, Magali Amiel, Laurence Kraus-Berthier, Marylore Chenel, Francois Bouzom, Michel Tod
S 55746 ((S)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide) is a new selective Bcl-2 inhibitor developed by Servier Laboratories and used to restore apoptosis functions in cancer patients. The aim of this work was to develop a translational approach using physiologically based (PB) pharmacokinetic (PK) modeling for interspecies extrapolation to anticipate the nonlinear PK behavior of this new compound in patients...
April 2, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Feng Xu, Liang Zhu, Chaoqun Qian, Junjie Zhou, Donghao Geng, Ping Li, Wenjing Xuan, Fangge Wu, Kaijing Zhao, Weimin Kong, Yuanyuan Qin, Limin Liang, Li Liu, Xiaodong Liu
Generally, diabetes remarkably alters expression and function of intestinal drug transporters. Nateglinide and bumetanide are substrates of monocarboxylate transporter 6 (MCT6). We aimed to report that diabetes downregulated function and expression of intestinal MCT6 and to investigate the possible mechanism in diabetic rats induced by combination of high-fat diet and low dose of streptozocin. The results indicated that diabetes significantly decreased oral plasma exposure of nateglinide. The plasma peak concentration and area under curve in diabetic rats were 16...
March 28, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Yu-Jie Chen, Jian Zhang, Ping-Ping Zhu, Xian-Wen Tan, Qiu-Hong Lin, Wen-Xia Wang, Shan-Shan Yin, Ling-Zhi Gao, Ming-Ming Su, Chang-Xiao Liu, Liang Xu, Wei Jia, Irina F Sevrioukova, Ke Lan
The primary bile acids (BAs) synthesized from cholesterol in the liver are converted to secondary BAs by gut microbiota. It was recently disclosed that the major secondary BA, deoxycholate (DCA) species, is stereoselectively oxidized to tertiary BAs exclusively by CYP3A enzymes. This work subsequently investigated the in vitro oxidation kinetics of DCA at C-1β, C-3β, C-4β, C-5β, C-6α, C-6β and C-19 in recombinant CYP3A enzymes and naive enzymes in human liver microsomes (HLMs). The stereoselective oxidations of DCA fit well with Hill kinetics at 1-300 μM in both recombinant CYP3A enzymes and pooled HLMs...
March 27, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Mengru Bai, Qingquan Zeng, Yingchun Chen, Mingyang Chen, Ping Li, Zhiyuan Ma, Dongli Sun, Hui Zhou, Caihong Zheng, Su Zeng, Huidi Jiang
L-Carnitine (L-Car) plays a crucial role in fatty acid β-oxidation. However, the plasma L-Car concentration in women markedly declines during pregnancy, the underlying mechanism and the consequent on maternal hepatic β-oxidation has not been clarified yet. Our results showed that the plasma L-Car level in mice at gestation day (GD) 18 was significantly lower than that in non-pregnant mice, and the mean fetal-to-maternal plasma L-Car ratio in GD 18 mice was 3.0. Carnitine/organic cation transporter 2 (OCTN2) was highly expressed in mouse and human placenta and up-regulated as gestation proceeds in human placenta, while carnitine transporter (CT) 1, CT2 and amino acid transporter B0, + (ATB0, + ) were extremely low...
March 27, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Colin James Henderson, Yury Kapelyukh, Nico Scheer, Anja Rode, Aileen W McLaren, Alastair Kenneth MacLeod, De Lin, Jayne Wright, Lesley Stanley, C Roland Wolf
Species differences in drug metabolism and disposition can confound the extrapolation of in vivo pharmacokinetic data to man, and also profoundly compromise drug efficacy studies due to differences in pharmacokinetics, in metabolites produced (which are often pharmacologically active) and in differential activation of the transcription factors CAR and PXR which regulate the expression of enzymes such as P450s and drug transporters. These differences have gained additional importance as a consequence of the use of genetically modified mouse models for drug efficacy testing and also patient-derived xenografts to predict individual patient responses to anti-cancer drugs...
March 25, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Dennis Allen Smith, Malcolm Rowland
The distribution of a drug within the body should be considered as involving movement of unbound drug between the various aqueous spaces of the body. At true steady state, even for a compound of restricted lipoidal permeability, unbound concentrations in all aqueous compartments (blood, extracellular, intracellular) are considered identical, unless a compartment has a clearance /transport process. In contrast, total drug concentrations may differ greatly reflecting binding or partitioning into constituents of each compartment...
March 25, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Pramod C Nair, Ross A McKinnon, John O Miners
Protein kinase inhibitors (KIs), which are mainly biotransformed by CYP3A4-catalyzed oxidation, represent a rapidly expanding class of drugs used primarily for the treatment of cancer. Ligand- and structure-based methods were applied here to investigate whether computational approaches may be employed to predict the site(s) of metabolism (SOM) of KIs, and to identify amino acids within the CYP3A4 active site involved in KI binding. A dataset of the experimentally determined SOMs of 31 KIs known to undergo biotransformation by CYP3A4 was collated...
March 22, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Sarah Dubaisi, Joseph A Caruso, Roger Gaedigk, Carrie A Vyhlidal, Philip C Smith, Ronald N Hines, Thomas A Kocarek, Melissa Runge-Morris
The liver is the predominant organ of metabolism for many endogenous and foreign chemicals. Cytosolic sulfotransferases (SULTs) catalyze the sulfonation of drugs and other xenobiotics, as well as hormones, neurotransmitters, and sterols, with consequences that include enhanced drug elimination, hormone inactivation, and pro-carcinogen bioactivation. SULTs are classified into six gene families, but only SULT1 and SULT2 enzymes are expressed in human liver. We characterized the developmental expression patterns of SULT1 and SULT2 mRNAs and proteins in human liver samples using quantitative RT-PCR (RT-qPCR), RNA sequencing, and targeted quantitative proteomics...
March 18, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Emi Kimoto, Manoli Vourvahis, Renato J Scialis, Heather Eng, A David Rodrigues, Manthena V S Varma
The aim of the present study was to quantitatively evaluate the drug-drug interactions (DDIs) of maraviroc (MVC) with various perpetrator drugs, including telaprevir (TVR), using in vitro data-informed physiologically based pharmacokinetic (PBPK) model. MVC showed significant active uptake and biliary excretion in sandwich-cultured human hepatocytes, and two-Km organic anion transporting polypeptide (OATP)1B1-mediated uptake in transfected cells (high-affinity Km ~5 μM). No measureable active uptake was noted in OATP1B3- and OATP2B1-transfceted cells...
March 12, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Shuai Wang, Buyun Chen, Peter Dragovich, Thomas Pillow, Leanna Staben, Jun Guo, Dian Su, Chenghong Zhang, Sudheer Bobba, Yong Ma, Jianshuang Wang, Dewakar Sangaraju, BinQing Wei, Gail Lewis Phillips, Cyrus Khojasteh, Donglu Zhang
Duocarmycins (including cyclopropyl pyrroloindole, CPI or cyclopropyl benzoindole, CBI) are a class of DNA minor groove alkylators and seco-CPI/CBIs are synthetic pro-forms that can spirocyclize to CPI/CBI. Bis-CPI/CBIs are potential drug candidates because of their enhanced cytotoxicity from DNA cross-linking, but are difficult to be analyzed for structure-activity correlation because of their DNA reactivity. To study its DNA alkylation, neutral thermal hydrolysis has been frequently applied to process depurination...
March 11, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Dafne Garcia-Mateos, Alba Maria Garcia-Lino, Indira Alvarez-Fernandez, Esther Blanco-Paniagua, Alvaro de la Fuente, Ana I Alvarez, Gracia Merino
Flunixin meglumine is a nonsteroidal anti-inflammatory drug (NSAID) widely used in veterinary medicine. It is indicated to treat inflammatory processes, pain and pyrexia in farm animals. In addition, it is one of the few NSAIDs approved for use in dairy cows, and consequently gives rise to concern regarding its milk residues. The ABCG2 efflux transporter is induced during lactation in the mammary gland and plays an important role in the secretion of different compounds into milk. Previous reports have demonstrated that bovine ABCG2 Y581S polymorphism increases fluoroquinolone levels in cow milk...
March 11, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Yuli Qian, Xinwen Wang, John S Markowitz
The escalating use of medical cannabis and significant recreational use of cannabis in recent years has led to higher potential for metabolic interactions between cannabis or one or more of its components and concurrently used medications. Although there have been a significant number of in vitro and in vivo assessments of the effects of cannabis on cytochrome P450 and UDP-glucuronosyltransferase enzyme systems, there is limited information regarding the effects of cannabis on the major hepatic esterase, carboxylesterase 1 (CES1)...
March 4, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Jean-Philippe Emond, Adrien Labriet, Sylvie Desjardins, Michele Rouleau, Lyne Villeneuve, Helene Hovington, Herve Brisson, Louis Lacombe, David Simonyan, Patrick Caron, Martine Perigny, Bernard Tetu, John K Fallon, Kathrin Klein, Philip C Smith, Uli Zanger, Chantal Guillemette, Eric Levesque
The accurate quantification of the metabolic enzyme UGT2B17 has been hampered by the high sequence identity with other UGT2B enzymes (as high as 94%) and by the lack of a specific antibody. Knowing the significance of the UGT2B17 pathway in drug and hormone metabolism and cancer, we developed a specific monoclonal antibody (EL-2B17mAb), initially validated by the lack of detection in liver microsomes of an individual carrying no UGT2B17 gene copy and in supersomes expressing UGT2B enzymes. Immunohistochemical detection in livers reveals a strong labeling of bile ducts and variable labeling of hepatocytes...
February 28, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Stephanie N Liu, Jessica Bo Li Lu, Christy Jw Watson, Philip Lazarus, Zeruesenay Desta, Brandon T Gufford
Integrase strand transfer inhibitor (INSTI)-based regimens dominate initial HIV treatment. Most INSTIs are metabolized predominantly via UDP-glucuronosyltransferases (UGTs). For drugs predominantly metabolized by UGTs, including INSTIs, in vitro data recovered from human hepatic microsomes (HLMs) alone often underpredict human oral clearance. While several factors may contribute, extrahepatic glucuronidation may contribute to this underprediction. Thus, we comprehensively characterized the kinetics for the glucuronidation of INSTIs (cabotegravir, dolutegravir, and raltegravir) using: pooled human microsomal preparations from liver (HLMs), intestinal (HIMs) and kidney (HKMs) tissues; HEK293 cells expressing individual UGTs; and recombinant UGTs (rUGTs)...
February 25, 2019: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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