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O A Makharin, V M Zhenilo, O Yu Patyuchenko
Quality anesthesia during surgery and in the postoperative period remains a topical problem of modern anesthesiology. The study of genetic characteristics of a patient is a goal that may be allow us to develop a personalized approach to solve this problem. The purpose of the review is a synthesis of literature data about the influence of genetic factors on pain perception and its treatment. The review included information obtained from SCOPUS, MedLine, EMBASE. The search keywords were: pain, pharmacogenetics, polymorphism, analgesics...
September 2017: Anesteziologiia i Reanimatologiia
Jessica H Brown, Prativa Das, Michael D DiVito, David Ivancic, Lay Poh Tan, Jason A Wertheim
A major challenge of maintaining primary hepatocytes in vitro is progressive loss of hepatocyte-specific functions, such as protein synthesis and cytochrome P450 (CYP450) catalytic activity. We developed a three-dimensional (3D) nanofibrous scaffold made from poly(L-lactide-co-glycolide) (PLGA) polymer using a newlyoptimizedwet electrospinning techniquethat resulted in a highly porous structure that accommodated inclusion of primary human hepatocytes. Extracellular matrix (ECM) proteins (type I collagen or fibronectin) at varying concentrations were chemically linked to electrospun PLGA using amine coupling to develop an in vitro culture system containing the minimal essential ECM components of the liver micro-environment that preserve hepatocyte function in vitro...
February 14, 2018: Acta Biomaterialia
Yuichi Yokoyama, Yoshifumi Sasaki, Natsuko Terasaki, Taku Kawataki, Koji Takekawa, Yumiko Iwase, Toshinobu Shimizu, Seigo Sanoh, Shigeru Ohta
Differentiated HepaRG cells maintain liver-specific functions such as drug-metabolizing enzymes. In this study, the feasibility of HepaRG cells as a human hepatocyte model for in vitro toxicity assessment was examined using selected hepatotoxic compounds. First, basal drug-metabolizing enzyme activities (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, uridine 5'-diphospho-glucuronosyltransferase [UGT], and sulfotransferases [SULT]) were measured in HepaRG, human hepatocytes, and HepG2 cells. Enzyme activities in differentiated HepaRG cells were comparable to those in human hepatocytes and much higher than those in HepG2 cells, except for SULT activity...
February 14, 2018: Biological & Pharmaceutical Bulletin
Jamie E Moscovitz, Amit S Kalgutkar, Kelly Nulick, Nathaniel Johnson, Zhiwu Lin, Theunis C Goosen, Yan Weng
The potential for drug-drug interactions (DDIs) arising from transcriptional regulation of drug disposition genes via activation of nuclear receptors (NRs) such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), and/or aryl hydrocarbon receptor (AhR) remains largely unexplored, as highlighted in a recent guidance document from the European Medicines Agency. The goal of this research was to establish PXR/CAR/AhR-specific drug metabolizing enzyme (DME) and transporter gene expression signatures in sandwich-cultured cryopreserved human hepatocytes using selective activators of PXR (rifampin), CAR (CITCO) and AhR (omeprazole)...
February 12, 2018: Journal of Pharmacology and Experimental Therapeutics
Sophie Gravel, Jean-Louis Chiasson, Suzanne Dallaire, Jacques Turgeon, Veronique Michaud
INTRODUCTION: Diabetes affects more than 9% of the adult population worldwide. Patients with type 2 diabetes mellitus (T2DM) show variable responses to some drugs which may be due, in part, to variability in the functional activity of drug-metabolising enzymes including cytochromes P450 (CYP450s). CYP450 is a superfamily of enzymes responsible for xenobiotic metabolism. Knowledge must be gained on the impact of T2DM and related inflammatory processes on drug metabolism and its consequences on drug response...
February 8, 2018: BMJ Open
Wufeng Fan, Guangming Ye
In order to identify the potential pathogenesis of hepatocellular carcinoma (HCC) developing from cirrhosis, a microarray‑based transcriptome profile was analyzed. The GSE63898 expression profile was downloaded from the Gene Expression Omnibus database, which included data from 228 HCC tissue samples and 168 cirrhotic tissue samples. The Robust Multi‑array Average in the Affy package of R was used for raw data processing and Student's t‑test was used to screen differentially expressed genes (DEGs). An enrichment analysis was then conducted using the Database for Annotation, Visualization and Integrated Discovery online tool, and the protein‑protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes and Cytoscape...
February 2, 2018: Molecular Medicine Reports
Burhan A Khan, Renee Robinson, Alison E Fohner, LeeAnna I Muzquiz, Brian D Schilling, Julie A Beans, Matthew J Olnes, Laura Trawicki, Holly Frydenlund, Cindi Laukes, Patrick Beatty, Brian Phillips, Deborah Nickerson, Kevin Howlett, Denise A Dillard, Timothy A Thornton, Kenneth E Thummel, Erica L Woodahl
Despite evidence that pharmacogenetics can improve tamoxifen pharmacotherapy, there are few studies with American Indian and Alaska Native (AIAN) people. We examined variation in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, and CYP2C9) and tamoxifen biotransformation in AIAN patients with breast cancer (n = 42) from the Southcentral Foundation in Alaska and the Confederated Salish and Kootenai Tribes in Montana. We tested for associations between CYP diplotypes and plasma concentrations of tamoxifen and metabolites...
February 13, 2018: Clinical and Translational Science
Yi-An Bi, Jian Lin, Sumathy Mathialagan, Laurie Tylaska, Ernesto Callegari, A David Rodrigues, Manthena V S Varma
Inter-individual variability in warfarin dose requirement demands personalized medicine approaches to balance its therapeutic benefits (anticoagulation) and bleeding risk. Cytochrome P450 2C9 (CYP2C9) genotype-guided warfarin dosing is recommended in the clinic, given the more potent S-warfarin is primarily metabolized by CYP2C9. However, only about 20-30% of inter-patient variability in S-warfarin clearance is associated with CYP2C9 genotype. We evaluated the role of hepatic uptake in the clearance of R- and S-warfarin...
February 12, 2018: Molecular Pharmaceutics
Agata Hanna Bryk, Ewa Wypasek, Krzysztof Plens, Magdalena Awsiuk, Anetta Undas
INTRODUCTION: Single nucleotide polymorphisms (SNP) in genes encoding proteins involved in metabolism and action of vitamin K antagonists (VKA) affect anticoagulation stability. We investigated how those polymorphisms influence bleeding rates in patients following venous thromboembolism (VTE). MATERIALS AND METHODS: In 324 patients following unprovoked VTE, 143 (44%) on warfarin and 181 (56%) on acenocoumarol, we recorded bleedings within the preceding 24 months...
February 9, 2018: Vascular Pharmacology
Jin Zeng, Yu-Juan Fan, Bo Tan, Hui-Zong Su, Yue Li, Lin-Lin Zhang, Jian Jiang, Fu-Rong Qiu
Cryptotanshinone (CT) is the main active component in the root of Salvia miltiorrhiza Bunge (SMB) that displays antibacterial, anti-inflammatory and anticancer activities. In this study, we characterized phase I and phase II metabolism of CT in human liver microsomes in vitro and identified the metabolic enzymes (CYPs and UGTs) involved. The metabolites of CT generated by CYPs were detected using LC-MS/MS and the CYP subtypes involved in the metabolic reactions were identified using chemical inhibitors of CYP enzymes and recombinant human CYP enzymes (CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4)...
February 8, 2018: Acta Pharmacologica Sinica
Rajanikanta Sahu, Tausif Ahmed, Ramchandra Sangana, Ravindra Punde, Bharat Bhusan Subudhi
Tinospora cordifolia (TC) has been used as a complimentary/alternative medicine against diabetes. Considering its potential to modulate metabolic enzymes, Tinospora cordifolia extract (TCE) may influence the metabolism of the antidiabeic drug Glibenclamide following co-administration. Accordingly, this work was undertaken to evaluate impact of TCE on fate of Glibenclamide. Activity of clinically important Cytochrome P450 isoenzymes were inhibited in the order of CYP2C9 > CYP2D6 > CYP2C19 > CYP1A2 > CYP3A4...
January 10, 2018: Journal of Pharmaceutical and Biomedical Analysis
Marin Roman, Diana Larisa Roman, Vasile Ostafe, Alecu Ciorsac, Adriana Isvoran
PURPOSE: The aim of this study is to use computational approaches to predict the ADME-Tox profiles, pharmacokinetics, molecular targets, biological activity spectra and side/toxic effects of 31 anabolic and androgen steroids in humans. METHODS: The following computational tools are used: (i) FAFDrugs4, SwissADME and admetSARfor obtaining the ADME-Tox profiles and for predicting pharmacokinetics;(ii) SwissTargetPrediction and PASS online for predicting the molecular targets and biological activities; (iii) PASS online, Toxtree, admetSAR and Endocrine Disruptomefor envisaging the specific toxicities; (iv) SwissDock to assess the interactions of investigated steroids with cytochromes involved in drugs metabolism...
February 5, 2018: Pharmaceutical Research
Carlo Federico Zambon, Vittorio Pengo, Stefania Moz, Dania Bozzato, Paola Fogar, Andrea Padoan, Mario Plebani, Francesca Groppa, Giovanni De Rosa, Roberto Padrini
PURPOSE: A previous trial failed to demonstrate the superiority of a demographic-genetic algorithm in predicting warfarin (W) dose over a standard clinical approach. The purpose of the present study is to re-analyse the results in subgroups of patients with differing baseline sensitivity to W, integrated with additional pharmacokinetic data. METHODS: The original trial allocated 180 treatment-naïve patients with non-valvular atrial fibrillation to a control arm (CTL, n = 92) or a genetic-guided arm (GEN, n = 88)...
February 2, 2018: European Journal of Clinical Pharmacology
Yi-Wen Zhang, Xiao-Wei Zheng, Yu-Jia Liu, Luo Fang, Zong-Fu Pan, Mei-Hua Bao, Ping Huang
Oridonin, the major terpene found in Rabdosia rubescens, is widely used as a dietary supplement or therapeutic drug. However, the effects of oridonin on major CYP450s are still unclear. As oridonin can enhance the effect of other clinical drugs, in this study, we investigated the influence of oridonin on CYP450s mRNA expression and its impact on activities in human HepaRG cell to evaluate the safety by studying its potential drug interaction. HepaRG cells were cultured with series concentrations of oridonin (1, 5, 10, and 20 μmol/L), and the major CYP450s mRNA and protein expression, as well as enzyme activities were analyzed by real-time polymerase chain reaction, Western blot analysis and UPLC-MS/MS-based metabolite assay...
January 26, 2018: Pharmacology
Raghava Choudary Palacharla, Parusharamulu Molgara, Hanumantha Rao Pathangi, Rajesh Kumar Boggavarapu, Arunkumar Manoharan, Ranjith Kumar Ponnamaneni, Devender Reddy Ajjala, Ramakrishna Nirogi
1. The objective is to evaluate methoxsalen as an in vitro phenotyping tool in comparison to ABT as a non-specific inactivator of P450 mediated metabolism. 2. The reversible inhibition of methoxsalen and ABT against the P450, FMO, AO, MAO A and B, enzymes was evaluated using standard marker probe reactions. The time dependent inhibition of P450 enzymes was evaluated in human liver microsomes. CES1 activities were determined by monitoring the depletion of known substrate, the clopidogrel. The metabolism of P450 substrates in the presence and absence of methoxsalen or ABT was evaluated in human liver microsomes...
January 31, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Sang-In Park, Ji-Young Park, Min-Ju Park, Sung-Vin Yim, Bo-Hyung Kim
Ojeok-san is a frequently used herbal medication for the management of osteoarthritic pain. We evaluated the effect of Ojeok-san on the pharmacokinetics of celecoxib at steady state in healthy subjects. An open-label, fixed-sequence, two-period, two-treatment cross-over study was conducted. In period I, the subjects received celecoxib capsule 200 mg once daily for 4 days. In period II, only Ojeok-san (14.47 g/pack, three times daily) was administered for 4 days, followed by co-administration with celecoxib for 4 days...
January 28, 2018: Basic & Clinical Pharmacology & Toxicology
Shuting Wang, Xiange Tang, Tingting Yang, Jiong Xu, Jiaxin Zhang, Xiaodong Liu, Li Liu
1. Contributions of cytochrome P450 (CYP450) isoforms to drug metabolism are often predicted using relative activity factor (RAF) method, assuming RAF values were independent of probe. We aimed to report probe-dependent characteristic of RAF values using CYP3A4 or CYP2C9 probes. 2. Metabolism of four CYP3A4 probes (testosterone, midazolam, verapamil, and atorvastatin) and three CYP2C9 probes (tolbutamide, diclofenac and S-warfarin) in human liver microsomes (HLM) and cDNA-expressed recombinant CYP450 (Rec-CYP450) systems were characterized and RAFCL value was estimated as ratio of probe intrinsic clearance in HLM to that in Rec-CYP450...
January 29, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Ryuta Asaumi, Kota Toshimoto, Yoshifusa Tobe, Kenta Hashizume, Ken-Ichi Nunoya, Haruo Imawaka, Wooin Lee, Yuichi Sugiyama
This study aimed to construct a physiologically based pharmacokinetic (PBPK) model of rifampicin that can accurately and quantitatively predict complex drug-drug interactions (DDIs) involving its saturable hepatic uptake and auto-induction. Using in silico and in vitro parameters, and reported clinical pharmacokinetic data, rifampicin PBPK model was built and relevant parameters for saturable hepatic uptake and UDP-glucuronosyltransferase auto-induction were optimized by fitting. The parameters for cytochrome P450 (CYP) 3A and CYP2C9 induction by rifampicin were similarly optimized using clinical DDI data with midazolam and tolbutamide as probe substrates, respectively...
January 25, 2018: CPT: Pharmacometrics & Systems Pharmacology
Shingen Misaka, Osamu Abe, Hideyuki Sato, Tomoyuki Ono, Yayoi Shikama, Satomi Onoue, Hirooki Yabe, Junko Kimura
PURPOSE: The objective of this study is to assess the effects of green tea and its major catechin component, (-)-epigallocatechin gallate (EGCG), on CYP2C9-mediated substrate metabolism in vitro, and the pharmacokinetics of fluvastatin in healthy volunteers. METHODS: The metabolism of diclofenac and fluvastatin in human recombinant CYP2C9 was investigated in the presence of EGCG. In a randomized three-phase crossover study, 11 healthy volunteers ingested a single 20-mg dose of fluvastatin with green tea extract (GTE), containing 150 mg of EGCG, along with water (300 mL), brewed green tea (300 mL), or water (300 mL) after overnight fasting...
January 24, 2018: European Journal of Clinical Pharmacology
Albert P Li, Ming-Chih David Ho, Kirsten Amaral, Carol Loretz
We report here a novel experimental system - MetMax™ cryopreserved human hepatocytes (MMHH), for in vitro drug metabolism studies. MMHH consist of cofactor-supplemented permeabilized cryopreserved human hepatocytes. The use procedures for MMHH are significantly simplified from that for conventional cryopreserved human hepatocytes (CCHH): 1. Storage at -80o C instead of in liquid nitrogen; 2. Usage directly after thawing without centrifugation and microscopic evaluation of cell density and viability and cell density adjustment...
January 23, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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