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Drug Metabolism and Disposition: the Biological Fate of Chemicals

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https://www.readbyqxmd.com/read/29237721/rev-erba-regulates-cyp7a1-through-repression-of-liver-receptor-homolog-1
#1
Tianpeng Zhang, Mengjing Zhao, Danyi Lu, Shuai Wang, Fangjun Yu, Lianxia Guo, Shijun Wen, Baojian Wu
REV-ERBα is a nuclear heme receptor (as known as a transcriptional repressor) that orchestrates circadian rhythms and cell metabolism. Here we investigate the role of LRH-1 in REV-ERBα regulation of CYP7A1 and cholesterol metabolism. We first characterized the tertiary amine GSK2945 as a highly specific Rev-erbα/REV-ERBα antagonist using cell-based assays and confirmed expression of Rev-erbα in mouse liver. GSK2945 treatment increased hepatic Cyp7a1 level and lowered plasma cholesterol in wild-type mice...
December 13, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29233819/characterization-of-interactions-among-cyp1a2-cyp2b4-and-nadph-cytochrome-p450-reductase-identification-of-specific-protein-complexes
#2
John Patrick Connick, James R Reed, Wayne L Backes
Cytochromes P450 catalyze oxygenation reactions via interactions with their redox partners. However, other proteins, particularly other P450s, also have been shown to form complexes that modulate P450 function. Previous studies showed that CYP1A2 and CYP2B4 form a complex when reconstituted into phospholipid vesicles; however, details of the interactions among the P450s and NADPH-cytochrome P450 reductase have not been fully characterized. The goal of this study was to examine P450 complex formation in living cells, using bioluminescence resonance energy transfer (BRET)...
December 12, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29233818/importance-of-the-unstirred-water-layer-and-hepatocyte-membrane-integrity-in-vitro-for-quantification-of-intrinsic-metabolic-clearance
#3
Francesca Leanne Wood, James Brian Houston, David Hallifax
Prediction of clearance - a vital component of drug discovery - remains in need of improvement and, in particular, requires more incisive assessment of mechanistic methodology in vitro, according to a number of recent reports. Although isolated hepatocytes have become an irreplaceable standard system for measurement of intrinsic hepatic clearance mediated by active uptake transport and metabolism, lack of prediction reliability appears to reflect a lack of methodological validation, especially for highly cleared drugs, as we have previously shown...
December 12, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29212823/quantitative-expression-of-hepatobiliary-transporters-and-functional-uptake-of-substrates-in-hepatic-2d-sandwich-cultures-a-comparative-evaluation-of-upcyte-and-primary-human-hepatocytes
#4
Michelle Schaefer, Gaku Morinaga, Akiko Matsui, Gerhard Schanzle, Daniel Bischoff, Roderich D Sussmuth
Deficient functional expression of drug transporters incapacitates most hepatic cell lines as reliable tool for evaluating transporter-mediated drug-drug interactions. Recently, genetically-modified cells, referred to as upcyte hepatocytes, have emerged as an expandable, non‑cancerous source of human hepatic cells. Herein, we quantified mRNA and protein levels of key hepatobiliary transporters and assessed associated uptake activity in short- and long-term cultures of upcyte human hepatocytes (UHH), in comparison to cryopreserved primary human hepatocytes (cPHH)...
December 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29212822/effect-of-probiotics-on-pharmacokinetics-of-orally-administered-acetaminophen-in-mice
#5
Jeon-Kyung Kim, Min Sun Choi, Jin-Ju Jeong, Su-Min Lim, In Sook Kim, Hye Hyun Yoo, Dong-Hyun Kim
Orally administered probiotics change gut microbiota composition and enzyme activities. Thus, coadministration of probiotics with drugs may lead to changes in the pharmacokinetic parameters of the drugs. In this study, we investigated the pharmacokinetics of acetaminophen in rats treated with probiotics. Oral administration of probiotics changed the gut microbiota composition in the mice. Of these probiotics, Lactobacillus reuteri K8 increased the numbers of clostridia, bifidobacteria, and enterococci, and Lactobacillus rhamnosus K9 decreased the number of bifidobacteria, determined by culturing in selective media...
December 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29196299/mrp3-transports-clopidogrel-aryl-glucuronide-from-the-hepatocytes-into-blood
#6
Jin-Zi Ji, Ting Tai, Bei-Bei Huang, Tong-Tong Gu, Qiong-Yu Mi, Hong-Guang Xie
Clopidogrel aryl glucuronide (CLP-G) is a major phase II metabolite of clopidogrel generated in the liver for further excretion into urine; however, it is unknown about how CLP-G transports from hepatocytes into blood. Because MRP3 is predominantly expressed in the sinusoidal side of hepatocytes, and preferentially transports glucuronide conjugates of drug metabolites from hepatocytes into bloodstream, it was hypothesized that MRP3 could be such an efflux transporter for CLP-G. In this study, the liver-to-plasma ratios of clopidogrel and its metabolites (including CLP-G) were compared between Abcc3 knock-out (KO) and wild-type (WT) mice, and ATP-dependent uptake of clopidogrel and CLP-G as well as estradiol-17-β-d-glucuronide into human recombinant MRP3 inside-out membrane vesicles was evaluated in the presence or absence of ATP...
December 1, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29162614/discovery-and-validation-of-pyridoxic-acid-and-homovanillic-acid-as-novel-endogenous-plasma-biomarkers-of-organic-anion-transporter-oat-1-and-oat3-in-cynomolgus-monkeys
#7
Hong Shen, David M Nelson, Regina V Oliveira, Yueping Zhang, Colleen A Mcnaney, Xiaomei Gu, Weiqi Chen, Ching Su, Michael D Reily, Petia A Shipkova, Jinping Gan, Yurong Lai, Punit Marathe, W Griffith Humphreys
Perturbation of OAT1- and OAT3-mediated transport can alter the exposure, efficacy, and safety of drugs. Although these have been reports of the endogenous biomarkers for OAT1/3, none of these have all of the characteristics required for a clinical useful biomarker. Cynomolgus monkeys were treated with intravenous probenecid (PROB) at a dose of 40 mg/kg in this study. As expected, PROB increased the AUC of co-administered furosemide (FSM), a known substrate of OAT1 and OAT3, by 4.1-fold, consistent with the values reported in humans (3...
November 21, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29162613/the-jak1-2-inhibitor-ruxolitinib-reverses-interleukin-6-mediated-suppression-of-drug-detoxifying-proteins-in-cultured-human-hepatocytes
#8
Marie Febvre-James, Arnaud Bruyere, Marc Le Vee, Olivier Fardel
The inflammatory cytokine interleukin (IL)-6, which basically activates the JAK/STAT signaling pathway, is well-known to repress expression of hepatic cytochromes P-450 (CYPs) and transporters. Therapeutic proteins, like mAbs targeting IL-6 or its receptor, have been consequently demonstrated to restore full hepatic detoxification capacity, which results in inflammatory disease-related drug-drug interactions (idDDIs). In the present study, we investigated whether ruxolitinib, a small drug acting as a JAK1/2 inhibitor and currently used in the treatment of myeloproliferative neoplasms, may also counteract IL-6 repressing effects towards hepatic detoxifying systems...
November 21, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29158248/pregnancy-increases-norbuprenorphine-clearance-in-mice-by-induction-of-hepatic-glucuronidation
#9
Michael Z Liao, Chunying Gao, Brian R Phillips, Naveen K Neradugomma, Lyrialle W Han, Deepak Kumar Bhatt, Bhagwat Prasad, Danny D Shen, Qingcheng Mao
Norbuprenorphine (NBUP) is the major active metabolite of buprenorphine (BUP) which is commonly used to treat opiate addiction during pregnancy; it possesses 25% of BUP's analgesic activity and 10 times BUP's respiratory depression effect. To optimize BUP's dosing regimen during pregnancy with better efficacy and safety, it is important to understand how pregnancy affects NBUP disposition. In this study, we examined the pharmacokinetics of NBUP in pregnant and non-pregnant mice by administering the same amount of NBUP through retro-orbital injection...
November 20, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29150544/estimation-of-circulating-drug-metabolite-exposure-in-human-using-in-vitro-data-and-physiologically-based-pharmacokinetic-modelling-example-of-a-high-metabolite-parent-drug-ratio
#10
R Scott Obach, Jian Lin, Emi Kimoto, Sridhar Duvvuri, Timothy Nicholas, Eugene P Kadar, Larry M Tremaine, Aarti Sawant Basak
TBPT ((R)-4-((4-(((4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol), a serotonin-4 receptor partial agonist, is metabolized to two metabolites: an N-dealkylation product (M1) and a cyclized oxazolidine structure (M2). After administration to humans, the exposure to M1 was low and the exposure to M2 was high, relative to the parent drug, despite this being the opposite in vitro. In this study, projection of the plasma metabolite/parent ratios for M1 and M2 was attempted, using in vitro metabolism, binding, and permeability data in static and dynamic PBPK models...
November 17, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29150543/toxicokinetics-and-physiologically-based-pharmacokinetic-modeling-of-the-shellfish-toxin-domoic-acid-in-nonhuman-primates
#11
Jing Jing, Rebekah Petroff, Sara Shum, Brenda Crouthamel, Ariel R Topletz, Kimberly S Grant, Thomas M Burbacher, Nina Isoherranen
Domoic acid (DA), a neurotoxin, is produced by marine algae and has caused toxications worldwide in animals and humans. However, the toxicokinetics of DA has not been fully evaluated, and information is missing on the disposition of DA following oral exposures at doses that are considered safe for human consumption. In this study, toxicokinetics of DA were investigated in cynomolgus monkeys, following single doses of 5 µg/kg DA iv, 0.075 mg/kg DA po and 0.15 mg/kg DA po. Following iv dosing, DA had a systemic clearance of 124 ± 71 ml/hr/kg, volume of distribution at steady state of 131±71 ml/kg and elimination half-life of 1...
November 17, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29138287/clopidogrel-carboxylic-acid-glucuronidation-is-mediated-mainly-by-ugt2b7-ugt2b4-and-ugt2b17-implications-for-pharmacogenetics-and-drug-drug-interactions
#12
Helina Kahma, Anne M Filppula, Mikko Neuvonen, E Katriina Tarkiainen, Aleksi Tornio, Mikko T Holmberg, Matti K Itkonen, Moshe Finel, Pertti J Neuvonen, Mikko Niemi, Janne T Backman
The antiplatelet drug clopidogrel is metabolized to an acyl-β-D-glucuronide, which causes time-dependent inactivation of CYP2C8. Our aim was to characterize the UDP-glucuronosyltransferase (UGT) enzymes that are responsible for the formation of clopidogrel acyl-β-D-glucuronide. Kinetic analyses and targeted inhibition experiments were performed using pooled human liver and intestine microsomes (HLM and HIM, respectively) and selected human recombinant UGTs based on preliminary screening. The effects of relevant UGT polymorphisms on the pharmacokinetics of clopidogrel were evaluated in 106 healthy volunteers...
November 14, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29138286/transporter-expression-in-non-cancerous-and-cancerous-liver-tissue-from-donors-with-hepatocellular-carcinoma-and-chronic-hepatitis-c-infection-quantified-by-lc-ms-ms-proteomics
#13
Sarah Billington, Adrian S Ray, Laurent Salphati, Guangqing Xiao, Xiaoyan Chu, W Griffith Humphreys, Mingxiang Liao, Caroline A Lee, Anita A Mathias, Cornelis E C A Hop, Christopher Rowbottom, Raymond Evers, Yurong Lai, Edward J Kelly, Bhagwat Prasad, Jashvant D Unadkat
Protein expression of major hepatobiliary drug transporters (NTCP, OATPs, OCT1, BSEP, BCRP, MATE1, MRPs and P-gp) in cancerous (C, n=8) and adjacent non-cancerous (NC, n=33) liver tissues obtained from chronic hepatitis C patients with hepatocellular carcinoma (HCV-HCC) were quantified by LC-MS/MS proteomics. Herein, we compare our results with our previous data from non-infected non-cirrhotic (control, n=36) and HCV-cirrhotic (n=30) livers. The amount of membrane protein yielded from NC and C HCV-HCC tissues decreased (31%, 67%) relative to control livers...
November 14, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29117990/simultaneous-physiologically-based-pharmacokinetic-pbpk-modeling-of-parent-and-active-metabolites-to-investigate-complex-cyp3a4-drug-drug-interaction-potential-a-case-example-of-midostaurin
#14
Helen Gu, Catherine Dutreix, Sam Rebello, Taoufik Ouatas, Lai Wang, Dung Yu Chun, Heidi J Einolf, Handan He
Midostaurin (PKC412) is being investigated for the treatment of acute myeloid leukemia (AML) and advanced systemic mastocytosis (advSM). It is extensively metabolized by cytochrome P450 (CYP) 3A4 to form 2 major active metabolites, CGP52421 and CGP62221. In vitro and clinical drug-drug interaction (DDI) studies indicated that midostaurin and its metabolites are substrates, reversible and time-dependent inhibitors, and inducers of CYP3A4. A simultaneous pharmacokinetic model of parent and active metabolites was initially developed by incorporating data from in vitro, preclinical, and clinical pharmacokinetic studies in healthy volunteers and in patients with AML or advSM...
November 8, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29109113/generation-and-characterization-of-sult4a1-mutant-mouse-models
#15
Patrick L Garcia, Mohammed I Hossain, Shaida A Andrabi, Charles N Falany
Sulfotransferase 4A1 (SULT4A1) belongs to the cytosolic sulfotransferase (SULT) superfamily of enzymes that catalyze sulfonation reactions with a variety of endogenous and exogenous substrates. Of the SULTs, SULT4A1 was shown to have the highest sequence homology between vertebrate species, yet no known function or enzymatic activity have been identified for this orphan SULT. To better understand SULT4A1 function in mammalian brain, two mutant SULT4A1 mouse strains were generated utilizing CRISPR-Cas9 technology...
November 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29101097/the-tripartite-motif-containing-24-acts-as-a-novel-coactivator-of-the-constitutive-active-androstane-receptor
#16
Yuichiro Kanno, Yuki Kure, Saori Kobayashi, Mariko Mizuno, Yumi Tsuchiya, Naoya Yamashita, Kiyomitsu Nemoto, Yoshio Inouye
The constitutive active/androstane receptor (CAR) is a nuclear receptor that acts as a transcription factor for a variety of genes, including genes encoding xenobiotic, steroid and drug-metabolizing enzymes and transporters. Transactivation of a target gene by a transcription factor is generally mediated through the concerted and stepwise recruitment of various proteins termed co-regulators, including coactivators and corepressors. In this study, tripartite motif containing 24 (TRIM24; also known as transcriptional intermediary factor 1 alpha) was found to interact with the CAR...
November 3, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29089306/organic-cation-transporter-1-is-responsible-for-hepatocellular-uptake-of-the-tyrosine-kinase-inhibitor-pazopanib
#17
Waleed Elsayed Ahmed Ellawatty, Yusuke Masuo, Ken-Ichi Fujita, Erina Yamazaki, Hiroo Ishida, Hiroshi Arakawa, Noritaka Nakamichi, Ramadan Abdelwahed, Yasutsuna Sasaki, Yukio Kato
Pazopanib is an orally active tyrosine kinase inhibitor that exhibits hepatotoxicity in some patients. Despite the clinical importance of its hepatic distribution, the transporter(s) responsible for hepatic uptake of pazopanib in humans remain undetermined. In order to characterize its hepatic uptake mechanism, we screened the effects of several transporter inhibitors, including tetrapentylammonium (TPeA) for organic cation transporters (OCTs) and cyclosporin A (CsA) for organic anion-transporting polypeptides (OATPs), on both plasma disappearance and hepatic distribution of pazopanib in mice after its intravenous administration...
October 31, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29084783/highlighting-vdr-targeted-activities-of-1%C3%AE-25-dihydroxyvitamin-d3-in-mice-via-physiologically-based-pharmacokinetic-pharmacodynamic-modeling
#18
Qi Joy Yang, Paola Bukuroshi, Holly P Quach, Edwin C Y Chow, K Sandy Pang
We expanded our published physiologically-based pharmacokinetic model on 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], ligand of the vitamin D receptor (VDR), to appraise VDR-mediated pharmacodynamics in mice. Since 1,25(OH)2D3 kinetics was best described by a segregated-flow intestinal model (SFM) that described a low/partial intestinal (blood/plasma) flow to enterocytes, with feedback regulation of its synthesis (Cyp27b1) and degradation (Cyp24a1) enzymes, this PBPK(SFM) model was expanded to describe the VDR-mediated changes (altered/basal mRNA expression) of target genes/responses with the indirect response model...
October 30, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29084782/successful-prediction-of-in-vivo-hepatobiliary-clearances-and-hepatic-concentrations-of-rosuvastatin-using-sandwich-cultured-rat-hepatocytes-transporter-expressing-cell-lines-and-quantitative-proteomics
#19
Kazuya Ishida, Mohammed Ullah, Beata Toth, Viktoria Juhasz, Jashvant D Unadkat
We determined whether in vivo transporter-mediated hepatobiliary clearance and hepatic concentrations of rosuvastatin (RSV) in the rat could be predicted by transport activity in sandwich-cultured rat hepatocytes (SCRH) and/or transporter-expressing cell lines scaled by differences in transporter protein expression between SCRH, cell lines, and rat liver. The predicted hepatobiliary clearances and hepatic concentrations of RSV were compared to our previously published PET imaging data. Sinusoidal uptake clearance (CLs,uptake) and efflux (canalicular and sinusoidal) clearances of [(3H)]-RSV in SCRH were evaluated in the presence and absence of Ca(2+) and in the absence and presence of 1 mM unlabeled RSV (to estimate passive diffusion clearance)...
October 30, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29070510/effect-of-flavin-containing-monooxygenase-fmo-genotype-mouse-strain-and-gender-on-trimethylamine-n-oxide-production-plasma-cholesterol-concentration-and-an-index-of-atherosclerosis
#20
Sunil Veeravalli, Kersti Karu, Flora Scott, Diede Fennema, Ian R Phillips, Elizabeth A Shephard
The objectives of the study were to determine the contribution, in mice, of members of the flavin-containing monooxygenase (FMO) family to the production of trimethylamine N-oxide (TMAO), a potential proatherogenic molecule, and whether, under normal dietary conditions, differences in TMAO production were associated with changes in plasma cholesterol concentration or with an index of atherosclerosis (Als). Concentrations of urinary trimethylamine (TMA) and TMAO and of plasma cholesterol were measured in 10-week-old male and female C57BL/6J and CD-1 mice and in mouse lines deficient in various Fmo genes (Fmo1(-/-), 2(-/-), 4(-/-) and Fmo5(-/-) )...
October 25, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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