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Drug Metabolism and Disposition: the Biological Fate of Chemicals

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https://www.readbyqxmd.com/read/28228413/determination-of-human-hepatic-cyp2c8-and-cyp1a2-age-dependent-expression-to-support-human-health-risk-assessment-for-early-ages
#1
Gina Song, Xueying Sun, Ronald N Hines, D Gail McCarver, Brian G Lake, Thomas G Osimitz, Moire R Creek, Harvey J Clewell, Miyoung Yoon
Predicting age-specific metabolism is important for evaluating age-related drug and chemical sensitivity. Multiple cytochrome P450s (CYP) and carboxylesterase (CES) enzymes are responsible for human pyrethroid metabolism. Complete ontogeny data for each enzyme is needed to support in vitro to in vivo extrapolation (IVIVE). This study was designed to determine age-dependent human hepatic CYP2C8 expression, for which only limited ontogeny data are available, and to further define CYP1A2 ontogeny. CYP2C8 and 1A2 protein levels were measured by quantitative Western blotting using liver microsomal samples prepared from 222 subjects with ages ranging from 8 weeks gestation to 18 years after birth...
February 22, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28209803/correlation-between-membrane-protein-concentrations-and-transcellular-transport-activity-for-breast-cancer-resistance-protein
#2
Houfu Liu, Liang Huang, Yi Li, Tingting Fu, Xueying Sun, Yan-Yan Zhang, Ruina Gao, Qingfang Chen, Wandong Zhang, Jasminder Sahi, Scott Summerfield, Kelly Dong
Emerging evidence indicates an important role for breast cancer resistance protein (BCRP) in limiting brain penetration of substrate drugs. While in vitro Transwell® assays can provide an indication of BCRP substrate potential, the predictability of these to in vivo brain penetration is still under debate. The present study examines the correlation of BCRP protein concentration and transcellular transport activity across MDCKII monolayers. We expressed human BCRP or murine Bcrp1 in MDCKII wild-type cells using BacMam2 virus transduction...
February 16, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28202577/nimesulide-and-4-hydroxynimesulide-as-bile-acid-transporters-inhibitors-are-contributory-factors-for-drug-induced-cholestasis
#3
Lei Zhou, Xiaoyan Pang, Jingfang Jiang, Dafang Zhong, Xiaoyan Chen
Nimesulide (NIM) is a classic nonsteroidal anti-inflammatory drug. However, some patients treated with NIM suffered from cholestatic liver injury. For this reason, we investigated the potential mechanism underlying NIM-induced cholestasis by using in vivo and in vitro models. Oral administration of 100 mg/kg/day NIM to Wistar rats for 5 days increased the levels of plasma total bile acids, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase by 1.49-, 1.31-, 1.60-, and 1.29-fold, respectively...
February 15, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28196829/marmoset-cytochrome-p450-3a4-expressed-in-liver-and-small-intestine-tissues-efficiently-metabolizes-midazolam-alprazolam-nifedipine-and-testosterone
#4
Shotaro Uehara, Yasuhiro Uno, Kazuyuki Nakanishi, Sakura Ishii, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
Common marmosets (Callithrix jacchus), small New World primates, are increasingly attracting attention as potentially useful animal models for drug development. However, characterization of cytochrome P450 (P450) 3A enzymes involved in the metabolism of a wide variety of drugs has remained in marmosets. In this study, sequence homology, tissue distribution, and enzymatic property of marmoset P450 3A4 orthologue, 3A5 orthologue, and 3A90 were investigated. Marmoset P450 3A forms exhibited high amino acid sequence identities (88-90%) to the human and cynomolgus monkey P450 3A orthologues and evolutionary closeness to human and cynomolgus monkey P450 3A orthologues, compared with other P450 3A enzymes...
February 14, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28188299/novel-mechanism-of-decyanation-of-gdc-0425-by-cytochrome-p450
#5
Ryan H Takahashi, Jason S Halladay, Michael Siu, Yuan Chen, Cornelis Eca Hop, Siamak Cyrus Khojasteh, Shuguang Ma
GDC-0425 is an orally bioavailable small molecule inhibitor of checkpoint kinase 1 (Chk1) that was investigated as a novel co-therapy to potentiate chemotherapeutic drugs such as gemcitabine. In the radiolabeled ADME study in Sprague-Dawley rats, trace level but long-lived 14C-labeled plasma thiocyanate was observed. This thiocyanate originated from metabolic decyanation of GDC-0425 and rapid conversion of cyanide to thiocyanate. Excretion studies indicated decyanation was a minor metabolic pathway, but placing 14C at nitrile magnified its observation...
February 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28188298/comparison-between-radioanalysis-and-19-f-nuclear-magnetic-resonance-spectroscopy-in-the-determination-of-mass-balance-metabolism-and-distribution-of-pefloxacin
#6
Haitao Hu, Kishore Kumar Katyayan, Boris A Czeskis, Everett J Perkins, Palaniappan Kulanthaivel
Mass balance and metabolism studies using radiolabeled substances are well recognized as an important part of the drug development process. Herein, we directly assessed the use of (19)F NMR to achieve quantitative mass balance, metabolism and distribution information for fluorinated compounds without the need for radiolabeled synthesis/study. As a test case, the disposition of pefloxacin, a fluoroquinolone antibiotic, was evaluated in rats using quantitative (19)F NMR in parallel with a radiolabeled study. Urine, bile, and feces samples were collected over specific periods following oral administration of either 25 mg/kg [(14)C]pefloxacin or 25 mg/kg pefloxacin and were subsequently profiled by radioactivity or (19)F NMR, respectively...
February 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28188297/alternative-splicing-in-the-cytochrome-p450-superfamily-expands-protein-diversity-to-augment-gene-function-and-redirect-human-drug-metabolism
#7
Andrew J Annalora, Craig B Marcus, Patrick L Iversen
The human genome encodes 57 cytochrome P450 (CYP) genes whose enzyme products metabolize hundreds of drugs, thousands of xenobiotics and unknown numbers of endogenous compounds including steroids, retinoids and icosinoids. Indeed, CYP genes are the first line of defense against daily environmental chemical challenges in a manner that parallels the immune system. Several databases, including PubMed, AceView, and Ensembl, were queried to establish a comprehensive analysis of the full human CYP transcriptome. This review describes a remarkable diversification of the 57 human CYP genes, which may be alternatively processed into nearly 1000 distinct mRNA transcripts to shape an individual's CYP proteome...
February 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28188296/effect-of-garlic-gingko-and-st-john-s-wort-extracts-on-the-pharmacokinetics-of-fexofenadine-a-mechanistic-study
#8
Jasmina Turkanovic, Jacobus P Gerber, Michael B Ward, Robert W Milne
The aim of this study was to determine the effects of garlic and ginkgo herbal extracts on the pharmacokinetics of the P-glycoprotein (P-gp)/Organic anion transporting polypeptides (Oatps) substrate fexofenadine. Male rats were dosed orally with garlic (120 mg/kg), ginkgo (17 mg/kg), St. John's wort (SJW; 1000 mg/kg; positive control) or milli Q water for 14 days. On day 15, rats were either administered fexofenadine (orally or intravenously), had their livers isolated and perfused with fexofenadine, or the small intestine divided into four segments (SI-SIV) and analysed for P-gp and Oatp1a5...
February 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28179375/quantitative-prediction-of-human-renal-clearance-and-drug-drug-interactions-of-organic-anion-transporter-substrates-using-in-vitro-transport-data
#9
Sumathy Mathialagan, Mary A Piotrowski, David A Tess, Bo Feng, John Litchfiled, Manthena V Varma
Organic anion transporters (OATs) play an important role in the renal secretion of drugs, and their functional change can result in pharmacokinetic variability. In this study, we applied transport rates measured using OAT-transfected human embryonic kidney cells to predict human renal secretory and total renal clearance of 31 diverse drugs. Selective substrates to OAT1 (tenofovir), OAT2 (acyclovir and ganciclovir) and OAT3 (benzylpenicillin, oseltamivir acid) were used to obtain relative activity factors (RAFs) for these individual transporters by relating in vitro transport clearance to in vivo secretory clearance...
February 8, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28167538/application-of-physiologically-based-pharmacokinetic-modeling-to-understanding-of-bosutinib-pharmacokinetics-prediction-of-drug-drug-and-drug-disease-interactions
#10
Chiho Ono, Poe-Hirr Hsyu, Richat Abbas, Cho-Ming Loi, Shinji Yamazaki
Bosutinib (Bosulif®) is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Ph+ chronic myelogenous leukemia. Bosutinib is predominantly metabolized by CYP3A4 as the primary clearance mechanism. The main objectives of the present study were to: 1) develop physiologically-based pharmacokinetic (PBPK) models of bosutinib, 2) verify and refine the PBPK models based upon clinical study results of bosutinib single-dose drug-drug interaction (DDI) with ketoconazole and rifampin, and single-dose drug-disease interaction (DDZI) in patients with renal and hepatic impairment, 3) apply the PBPK models to predict DDI outcome in patients with weak and moderate CYP3A inhibitors, and 4) apply the PBPK models to predict DDZI outcomes in renally and hepatically impaired patients after multiple-dose administration...
February 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28153842/regional-expression-levels-of-drug-transporters-and-metabolizing-enzymes-along-the-pig-and-human-intestinal-tract-and-comparison-with-caco-2-cells
#11
Stefan F C Vaessen, Marola M H van Lipzig, Raymond H H Pieters, Cyrille A M Krul, Heleen M Wortelboer, Evita van de Steeg
Intestinal transporter proteins and metabolizing enzymes play a crucial role in the oral absorption of a wide variety of drugs. The aim of the current study was to better characterize available intestinal in vitro models by comparing expression levels of these proteins and enzymes between porcine intestine, human intestine and Caco-2 cells. We therefore determined the absolute protein expression of 19 drug transporters and the mRNA expression of 12 metabolic enzymes along the pig intestinal tract (duodenum, jejunum, ileum; N=4), in human intestine (jejunum; N=9) and Caco-2 cells...
February 2, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28153841/cholic-acid-feeding-leads-to-increased-cyp2d6-expression-in-cyp2d6-humanized-mice
#12
Xian Pan, Rebecca Kent, Kyoung-Jae Won, Hyunyoung Jeong
Cytochrome P450 2D6 (CYP2D6) is a major drug-metabolizing enzyme, but factors governing transcriptional regulation of its expression remain poorly understood. Based on previous reports of small heterodimer partner (SHP) playing an important role as a transcriptional repressor of CYP2D6 expression, here we investigated how a known upstream regulator of SHP expression, namely cholestasis triggered by cholic acid (CA) feeding in mice, can lead to altered CYP2D6 expression. To this end, CYP2D6-humanized (Tg-CYP2D6) mice were fed with CA-supplemented or control diet for 14 days, and hepatic expression of multiple genes was examined...
February 2, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28137721/transcriptional-functional-and-mechanistic-comparisons-of-stem-cell-derived-hepatocytes-heparg-cells-and-3d-human-hepatocyte-spheroids-as-predictive-in-vitro-systems-for-drug-induced-liver-injury
#13
Catherine C Bell, Volker M Lauschke, Sabine U Vorrink, Henrik Palmgren, Roger Duffin, Tommy B Andersson, Magnus Ingelman-Sundberg
Reliable and versatile hepatic in vitro systems for the prediction of drug pharmacokinetics and toxicity are essential constituents of preclinical safety assessment pipelines for new medicines. Here, we compared three emerging cell systems, hepatocytes derived from induced pluripotent stem cells (hiPS-Hep), HepaRG cells and 3D primary human hepatocyte (PHH) spheroids at transcriptional and functional levels in a multi-center study to evaluate their potential as predictive models for drug-induced hepatotoxicity...
January 30, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28122787/a-physiologically-based-pharmacokinetic-modeling-approach-to-predict-drug-drug-interactions-of-sonidegib-lde225-with-perpetrators-of-cyp3a-in-cancer-patients
#14
Heidi J Einolf, Jocelyn Zhou, Christina Won, Lai Wang, Sam Rebello
Sonidegib (Odomzo®) is an orally available Smoothened inhibitor for the treatment of advanced basal cell carcinoma. Sonidegib was found to be metabolized primarily by cytochrome P450 (CYP)3A in vitro The effect of multiple doses of the strong CYP3A perpetrators, ketoconazole (KTZ) and rifampin (RIF), on sonidegib pharmacokinetics (PK) after a single 800 mg dose in healthy subjects was therefore assessed. This data was used to verify a physiologically-based pharmacokinetic (PBPK) model developed to: 1) bridge the clinical drug-drug interaction (DDI) study of sonidegib with KTZ and RIF in healthy subjects to the marketed dose (200 mg) in patients, 2) predict acute (14 days) versus long-term dosing of the perpetrators with sonidegib at steady-state, and 3) predict the effect of moderate CYP3A perpetrators on sonidegib exposure in patients...
January 25, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28122786/determination-of-incubational-binding-in-in-vitro-microsomal-and-hepatocyte-metabolic-stability-incubations-a-comparison-of-methods
#15
Sofia Chen, Luna Prieto Garcia, Fredrik H Bergstrom, Par Nordell, Ken Grime
Fraction of drug unbound in an in vitro intrinsic clearance (CLint) incubation, fuinc, is an important parameter in the pursuit of accurate clearance predictions and is often predicted using algorithms based on drug lipophilicity measures. Analysis of AstraZeneca's database suggests that simple lipophilicity alone is a relatively poor predictor. Fuinc is typically measured using equilibrium dialysis binding assays but can be measured directly in CLint assays using multiple concentrations of hepatocytes or microsomal protein...
January 25, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28069721/specific-inhibition-of-the-distribution-of-lobeglitazone-to-the-liver-by-atorvastatin-in-rats-evidence-for-an-roatp1b2-mediated-interaction-in-hepatic-transport
#16
Chang-Soon Yim, Yoo-Seong Jeong, Song-Yi Lee, Wonji Pyeon, Heon-Min Ryu, Jong-Hwa Lee, Kyeong-Ryoon Lee, Han-Joo Maeng, Suk-Jae Chung
CYP enzymes and hOATP1B1 are reported to be involved in the pharmacokinetics of lobeglitazone (LB), a new PPARγ agonist. Atorvastatin (ATV), a substrate for CYP3A and hOATP1B1, is likely to be co-administered with LB in patients with the metabolic syndrome. We report herein on a study of potential interactions between LB and ATV in rats. When LB was IV-administered with ATV, the systemic clearance (CL; 2.67 ± 0.63 mL/min/kg) and volume of distribution at steady-state (Vss; 289 ± 20 mL/kg) for LB remained unchanged, compared to those of LB without ATV (CL, 2...
January 9, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28069720/pregnancy-increases-the-renal-secretion-of-n1-methylnicotinamide-an-endogenous-probe-for-renal-cation-transporters-in-patients-prescribed-metformin
#17
Mackenzie C Bergagnini-Kolev, Mary F Hebert, Thomas R Easterling, Yvonne S Lin
N1-methylnicotinamide (1-NMN) has been investigated as an endogenous probe for the renal transporter activity of organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins 1 and 2-K (MATE1 and MATE2-K). As pregnancy increased the renal secretion of metformin, a substrate for OCT2, MATE1 and MATE2-K, we hypothesized that the renal secretion of 1-NMN would be similarly affected. Blood and urine samples collected from women prescribed metformin for type 2 diabetes, gestational diabetes and polycystic ovarian syndrome (PCOS) during early-, mid-, and late-pregnancy (n = 34 visits) and postpartum (n=14 visits) were analyzed for 1-NMN using liquid chromatography-mass spectrometry...
January 9, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28062543/multiple-slc-and-abc-transporters-contribute-to-the-placental-transfer-of-entecavir
#18
Zhiyuan Ma, Xi Yang, Ting Jiang, Mengru Bai, Caihong Zheng, Su Zeng, Dongli Sun, Huidi Jiang
Entecavir (ETV), a nucleoside analogue with high efficacy against hepatitis B virus, is recommended as a first-line antiviral drug for the treatment of chronic hepatitis B. However, scant information is available on the use of ETV in pregnancy. To better understand the safety of ETV in pregnant women, we aimed to demonstrate whether ETV could permeate placental barrier and the underlying mechanism. Our study showed that small amount of ETV could permeate across placenta in mice. ETV accumulation in activated or non-activated BeWo cells (treated with or without forskolin) was sharply reduced in the presence of 100 μM of adenosine, cytidine and in Na+ free medium, indicating that nucleoside transporters possibly mediate the uptake of ETV...
January 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28062542/phenobarbital-treatment-at-a-neonatal-age-results-in-decreased-efficacy-of-omeprazole-in-adult-mice
#19
Yun-Chen Tien, Stephanie C Piekos, Chad Pope, Xiao-Bo Zhong
Drug-drug interactions (DDIs) occur when the action of one drug interferes with or alters the activity of another drug taken concomitantly. This can lead to decreased drug efficacy or increased toxicity. Because of DDIs, physicians in the clinical practice attempt to avoid potential interactions when multiple drugs are co-administrated, however there is still a large knowledge gap in understanding how drugs taken in the past can contribute to DDIs in the future. The goal of this study is to investigate the consequence of neonatal drug exposure on efficacy of other drugs administered to adult life...
January 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28062541/evaluation-of-a-novel-renewable-hepatic-cell-model-for-prediction-of-clinical-cyp3a4-induction-using-a-correlation-based-ris-approach
#20
Rongjun Zuo, Feng Li, Sweta Parikh, Li Cao, Kirsten L Cooper, Yulong Hong, Jin Liu, Ronald A Faris, Daochuan Li, Hongbing Wang
Metabolism enzyme induction-mediated drug-drug interactions need to be carefully characterized in vitro for drug candidates in order to predict in vivo outcomes of safety risk and therapeutic efficiency. Currently, both the FDA and EMA recommend using primary human hepatocytes as the "Gold Standard" in vitro test system for studying the induction potential of candidate drugs on cytochrome P450 (CYP), CYP3A4, CYP1A2, and CYP2B6. However, primary human hepatocytes are known to bear inherent limitations such as limited supply and large lot-to-lot variations which result in an experimental burden to qualify new lots...
January 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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