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Drug Metabolism and Disposition: the Biological Fate of Chemicals

Albert P Li, Novera Alam, Kirsten Amaral, Ming-Chih David Ho, Carol Loretz, Walter Mitchell, Qian Yang
We report here a novel in vitro enteric experimental system, cryopreserved human intestinal mucosa (CHIM), for the evaluation of enteric drug metabolism, drug-drug interaction, drug toxicity, and pharmacology. CHIM were isolated from the small intestines of four human donors. The small intestines were first dissected into duodenum, jejunum and ileum, followed by collagenase digestion of the intestinal lumens. The isolated mucosa were gently homogenized to yield multiple cellular fragments followed by cryopreservation in a programmable liquid cell freezer and stored in liquid nitrogen...
July 13, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Jie Pu, Fen Wang, Wei Tang, Mingshe Zhu
Ilaprazole is a new proton pump inhibitor (PPI) and currently marketed in China and South Korea for the treatment of gastric and duodenal ulcer. Ilaprazole has a favorable long half-life and minimal pharmacokinetic variability associated with CYP2C19 polymorphism. Sulfoxide oxidation of ilaprazole is catalyzed mainly by CYP3A4. Thus, it has been widely accepted that CYP3A4 plays the major role in the clearance of ilaprazole in human. However, ADME data of radiolabeled ilaprazole in human are not available and ilaprazole exposure to human is not elevated by a co-administered potent CYP3A4 inhibitor...
July 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Birgit M Wollmann, Silje Watterdal Syversen, Maria Vistnes, Elisabeth Lie, Lise L Mehus, Espen Molden
Systemic inflammation has been linked to suppressed CYP3A4 activity. The aim of this study was to examine associations between levels of a broad selection of cytokines and CYP3A4 phenotype in patients with rheumatoid arthritis (RA). The study included 31 RA patients treated with tumor necrosis factor (TNF)-α inhibitors. CYP3A4 phenotype was measured as serum concentration of 4β-hydroxycholesterol (4βOHC) by UPLC-MS/MS in samples collected prior to and 3 months after initiation of treatment with TNF-α inhibitors...
July 10, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Malika P Godamudunage, Anne M Grech, Emily E Scott
Adult drug metabolism is dominated by cytochrome P450 3A4 (CYP3A4), which is often inhibited by antifungal azole drugs, resulting in potential alterations in drug metabolism and adverse drug/drug interactions. In the fetal and neonatal stages of life, expression of CYP3A4 is replaced by the 87%-identical cytochrome P450 3A7 (CYP3A7). Azole antifungals developed for adults are also used in neonates assuming they interact similarly with both enzymes, but systematic information is lacking. Herein a method was developed for generating recombinant purified CYP3A7...
July 10, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Xiangyu Hou, Jialan Zhou, Songda Yu, Lei Zhou, Yifan Zhang, Dafang Zhong, Xiaoyan Chen
Imrecoxib is a typical cyclooxygenase-2 inhibitor and the benzylic carbon motif is its major site of oxidative metabolism, producing a hydroxymethyl metabolite (M1) and a carboxylic acid metabolite (M2). The plasma exposure of M2 is both four times higher than those of M0 and M1 in humans. However, this metabolite is rarely formed in in vitro experiments. Therefore, the present study aims to investigate the formation mechanism of M2, and to further elucidate the reason for the discrepancy between in vitro and in vivo metabolic data...
July 6, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Duan Liu, Sisi Qin, Bamiki Ray, Krishna R Kalari, Liewei Wang, Richard M Weinshilboum
CYP1A1 expression can be up-regulated by the ligand-activated aryl hydrocarbon receptor (AHR). Based on prior observations with estrogen receptors and estrogen response elements, we tested the hypothesis that single-nucleotide polymorphisms (SNPs) mapping hundreds of base pairs (bp) from xenobiotic response elements (XREs) might influence AHR binding and subsequent gene expression. Specifically, we analyzed DNA sequences 5 Kb up- and down-stream of the CYP1A1 gene for putative XREs. SNPs located ±500 bp of these putative XREs were studied using a genomic data-rich human lymphoblastoid cell line (LCL) model system...
July 6, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Michele Fedecostante, Koen Westphal, Michele Buono, Natalia Sanchez Romero, Martijn J Wilmer, Janis Kerkering, Pedro Miguel Baptista, Joost G Hoenderop, Rosalinde Masereeuw
Drug-induced kidney injury (DIKI) in medicinal compound development accounts for over 20% of clinical trials failure and involves damage to different nephron segments, mostly the proximal tubule. Yet, currently applied cell models fail to reliably predict nephrotoxicity nor are easy to establish. Here, we developed a novel three-dimensional (3D) nephrotoxicity platform based on decellularized rat kidneys scaffolds (DS) recellularized with conditionally immortalized human renal proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC-OAT1)...
July 6, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Tingting Yan, Hong Wang, Lijuan Cao, Qiong Wang, Shogo Takahashi, Tomoki Yagai, Guolin Li, Kristopher W Krausz, Guangji Wang, Frank J Gonzalez, Haiping Hao
Non-alcoholic steatohepatitis (NASH) is the progressive stage of non-alcoholic fatty liver disease that may ultimately lead to cirrhosis and liver cancer, and there are few therapeutic options for its treatment. Glycyrrhizin (GL), extracted from the traditional Chinese medicine (TCM) liquorice, has potent hepatoprotective effects in both preclinical animal models and in humans. However, little is known about its effects and mechanisms in treating NASH. To explore the effects of GL on NASH, GL or its active metabolite glycyrrhetinic acid (GA), was administered to mice treated with a methionine-choline-deficient (MCD) diet-induced NASH model, and histological and biochemical analyses used to measure the degree of lipid disruption, liver inflammation and fibrosis...
June 29, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Jane R Kenny, Diane Ramsden, David B Buckley, Shannon Dallas, Conrad Fung, Michael Mohutsky, Heidi J Einolf, Liangfu Chen, Joshua G Dekeyser, Maria Fitzgerald, Theunis C Goosen, Y Amy Siu, Robert L Walsky, George Zhang, Donald Tweedie, Niresh Hariparsad
The IQ induction working group presents an assessment of best practice for data interpretation of in vitro induction, specifically, response thresholds, variability, application of controls and translation to clinical risk assessment with focus on CYP3A4 mRNA. Single concentration control data and Emax/EC50 data for prototypical CYP3A4 inducers were compiled from many human hepatocyte donors in different laboratories. Clinical CYP3A induction and in vitro data were gathered for 51 compounds, 16 of which were proprietary...
June 29, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Chen Xu, Jie Gao, Hai-Feng Zhang, Na Gao, Yuan-Yuan Guo, Yan Fang, Qiang Wen, Hai-Ling Qiao
UDP-glucuronosyltransferase 2B7 (UGT2B7) is one of the most significant isoforms of UGTs in human liver. This research measured UGT2B7 protein content and activities including Vmax and CLint in human liver at isoform, microsomal, liver tissue, and liver levels and identified the factors that influence expression. We determined absolute protein content by LC-MS/MS and activities using the probe drug Zidovudine in 82 normal human liver microsomes. Using a bottom-up method for derivation, we showed UGT2B7 content at the microsomal, liver tissue, and liver levels, as well as activities at the isoform, microsomal, liver tissue, and liver levels in vitro, and predicted hepatic clearance in vivo, with median, range, variation, and 95 and 50% prediction intervals...
June 21, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Tashinga E Bapiro, Andy Sykes, Scott Martin, Michael Davies, James Wt Yates, Matthias Hoch, Helen E Rollison, Barry Jones
AZD9496 is an oral selective estrogen receptor degrader currently in clinical development for treatment of estrogen receptor positive breast cancer. In a first-in-human Phase 1 study, AZD9496 exhibited dose non-linear pharmacokinetics whose mechanistic basis was investigated in this study. The metabolism kinetics of AZD9496 were studied using human liver microsomes (HLM), recombinant cytochrome P450s (rCYPs) and hepatocytes. In addition, modelling approaches were used to gain further mechanistic insights. CYP2C8 was predominantly responsible for biotransformation of AZD9496 to its two main metabolites whose rate of formation with increasing AZD9496 concentrations exhibited complete substrate inhibition in HLM, rCYP2C8 and hepatocytes...
June 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Cassandra Johnson, Alexander J Prokopienko, Raymond E West, Thomas D Nolin, Jason R Stubbs
Circulating trimethylamine N-oxide (TMAO) predicts poor cardiovascular outcomes in patients with chronic kidney disease (CKD). Accumulation of serum TMAO has been observed in CKD patients; however, the mechanisms contributing to this finding have been inadequately explored. The purpose of this study was to investigate the mechanisms responsible for TMAO accumulation in the setting of decreased kidney function using a CKD mouse model. Mice were fed a diet supplemented with 0.2% adenine to induce CKD, which resulted in increased serum TMAO concentrations (Females: CKD 29...
June 18, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
David J Wagner, Laura M Shireman, Sojung Ahn, Danny D Shen, Joanne Wang
Methamphetamine is one of the most widely abused illicit drugs. While human intoxication and multiple tissue toxicities frequently occur in abusers, little is known about the distribution of methamphetamine or its primary metabolites, amphetamine and para -hydroxymethamphetamine ( p -OHMA), to their sites of toxicity. This study determined the pharmacokinetics, tissue exposure, and partition ratios of methamphetamine and major metabolites in various mouse tissues and investigated the impact of organic cation transporter 3 (Oct3) following intravenous injection of methamphetamine to male Oct3 +/+ and Oct3 -/- mice...
June 18, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Venkatesh Pilla Reddy, Barry C Jones, Nicola Colclough, Abhishek Srivastava, Joanne Wilson, Danxi Li
Our recent paper (Jones et al., 2017) demonstrated the ability to predict in vivo clearance of Flavin-containing Monooxygenases (FMO) drug substrates, using in vitro human hepatocyte and human liver microsomal intrinsic clearance (CLint) with standard scaling approaches. In this paper, we apply physiologically based pharmacokinetic (PBPK) modelling & simulation approaches (M&S) to predict the clearance, AUC and Cmax together with the plasma profile of a range of drugs from the original study. The human physiological parameters for FMO, such as enzyme abundance in liver, kidney, gut were derived from in vitro data and clinical pharmacogenetics studies...
June 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Kazuya Ishida, Mohammed Ullah, Beata Toth, Viktoria Juhasz, Jashvant D Unadkat
For successful in vitro -to- in vivo extrapolation (IVIVE) of hepatic drug uptake and DDI, it is important to characterize the kinetic properties of the individual transporters involved, their fraction (ft) contribution to hepatic uptake, and their selective inhibitors. Here, we characterized the in vitro transport kinetics of two model drugs, rosuvastatin (RSV) and olmesartan acid (OLM), by rat hepatic organic anion transporting polypeptides (Oatp1a1, 1a4 and 1b2) and identified selective inhibitors of these transporters...
June 11, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Stephanie C Piekos, Liming Chen, Pengcheng Wang, Jian Shi, Sharon Yaqoob, Hao-Jie Zhu, Xiaochao Ma, Xiao-Bo Zhong
The induction of cytochrome P450 enzymes (CYPs) in response to drug treatment is a significant contributing factor to drug-drug interactions, which may reduce therapeutic efficacy and/or cause toxicity. As most studies on CYP induction are performed in adults, enzyme induction at neonatal, infant, and adolescent ages is not well understood. Previous work defined the postnatal ontogeny of drug-metabolizing CYPs in human and mouse livers; however, there are limited data on the ontogeny of the induction potential of each enzyme in response to drug treatment...
June 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Hiroyuki Yamaguchi, Toshiaki Takezawa
A collagen vitrigel membrane (CVM) we developed can function as both a scaffold for cells and a pathway for chemicals. To extrapolate the corneal permeability of chemicals in vivo, we proposed six corneal models using the CVM. Thin and thick CVMs were utilized as models for Bowman's membrane (BM) and an acellular-stroma (AS), respectively. Models for a corneal epithelium (CEpi), a corneal epithelium-acellular stroma (CEpi-AS), a corneal epithelium-endothelium (CEpi-Endo) and a corneal epithelium-acellular stroma-endothelium (CEpi-AS-Endo) were fabricated by culturing corneal epithelial cells and/or corneal endothelial cells on the surface of CVMs...
May 29, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Michele Visentin, Angelo Torozi, Zhibo Gai, Stephanie Hausler, Chao Li, Christian Hiller, Peter H Schraml, Holger Moch, Gerd A Kullak-Ublick
[18 F]fluorocholine is the fluorinated analogue of [11 C]choline and is used in positron emission tomography (PET) to monitor tumor metabolic activity. While important to optimize its use and expand the clinical indications, the molecular determinants of fluorocholine cellular uptake are poorly characterized. Here, we described the influx kinetics of fluorocholine mediated by the organic cation transporter 2 (OCT2, SLC22A2) and compared with that of choline. Then, we characterized the expression pattern of OCT2 in renal cell carcinoma (RCC)...
May 24, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Sarah M Glass, Cydney M Martell, Alexandria K Oswalt, Victoria Osorio-Vasquez, Christi Cho, Michael J Hicks, Jacqueline M Mills, Rina Fujiwara, Michael J Glista, Sharat S Kamath, Laura Lowe Furge
Metabolic phenotype can be affected by multiple factors including allelic variation and interactions with inhibitors. Human CYP2D6 is responsible for approximately 20% of CYP-mediated drug metabolism but consists of over 100 known variants with several variants being commonly found in the population and others quite rare. Four CYP2D6 allelic variants - three with a series of mutations distal to the active site (*34, *17-2, *17-3) and one ultra-metabolizer with mutations near the active site (*53), along with reference *1 and an active site mutant of *1 (Thr309Ala) were expressed, purified, and studied for interactions with the typical substrates dextromethorphan and bufuralol and the inactivator SCH 66712...
May 21, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Yuki Yamasaki, Kaoru Kobayashi, Fuka Okuya, Naoyo Kajitani, Kanako Kazuki, Satoshi Abe, Shoko Takehara, Shingo Ito, Seiryo Ogata, Tatsuki Uemura, Sumio Ohtsuki, Genki Minegishi, Hidetaka Akita, Kan Chiba, Mitsuo Oshimura, Yasuhiro Kazuki
P-glycoprotein (P-gp), encoded by the MDR1 gene in humans and by the Mdr1a/1b genes in rodents, is expressed in numerous tissues and plays as an efflux pump to limit the distribution and absorption of many drugs. Owing to species differences of P-gp between humans and rodents, it is difficult to predict the impact of P-gp on pharmacokinetics and tissue distribution of P-gp substrates in humans from results of animal experiments. Therefore, we generated a novel P-gp humanized mouse model by using a mouse artificial chromosome (MAC) vector [designated human MDR1-MAC (hMDR1-MAC) mice]...
May 18, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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