A Novel In vitro Experimental System for the Evaluation of Enteric Drug Metabolism: Cofactor-Supplemented Permeabilized Cryopreserved Human Enterocytes (MetMax™ Cryopreserved Human Enterocytes).

Drug metabolism letters Pub Date : 2018-01-01 DOI:10.2174/1872312812666180820142141

Albert P Li, Kirsten Amaral, Ming-Chih D Ho

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引用次数: 9

Abstract

Background: We report here an evaluation of a novel experimental system- cofactorsupplemented permeabilized cryopreserved human enterocytes (MetMax™ cryopreserved human enterocytes (MMHE), patent pending) for applications in the evaluation of enteric drug metabolism. A major advantage of MMHE over Conventional Cryopreserved Human Enterocytes (CCHE) is the simplification of the use procedures including storage at -80°C instead of in liquid nitrogen, and use of the cells immediately after thawing without a need for centrifugation and microscopic evaluation of cell density and viability and cell density adjustment.

Methods: In this study, we compared MMHE and CCHE in key phase 1 oxidation and phase 2 conjugation Drug Metabolism Enzyme (DME) activities that we recently reported for cryopreserved human enterocytes: CYP2C9 (diclofenac 4'- hydroxylation), CYP2C19 (s-mephenytoin hydroxylation), CYP3A4 (midazolam 1'-hydroxylation), CYP2J2 (astemizole O-demethylation), uridine 5'-diphosphoglucuronosyltransferase (UGT; 7-hydroxycoumarin glucuronidation), sulfotransferase (SULT; 7- hydroxycoumarin sulfation), N-acetyl transferase-1 (NAT-1; p-benzoic acid N-acetylation), and carboxyesterase- 2 (CES-2; hydrolysis of irinotecan to SN38). Both CCHE and MMHE were active in all the DME pathways evaluated, with specific activities of MMHE ranged from 142% (CYP2C9) to 1713% (UGT) of that for CCHE. β-hydroxylation and testosterone 6.

Result and conclusion: Our results suggest that the MMHE system represents a convenient and robust in vitro experimental system for the evaluation of enteric drug metabolism.

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一种评估肠内药物代谢的新型体外实验系统:辅助因子补充通透性低温保存人肠细胞(MetMax™Cryopreserved Human Enterocytes)。

背景:我们在此报告了一种新的实验系统的评估-辅酶补充通透性冷冻保存人肠细胞(MetMax™冷冻保存人肠细胞(MMHE)，专利申请中)用于评估肠道药物代谢的应用。MMHE与传统的冷冻保存人肠细胞(CCHE)相比的一个主要优势是简化了使用程序，包括在-80°C而不是液氮中储存，并且在解冻后立即使用细胞，而无需离心和显微镜下评估细胞密度和活力以及细胞密度调整。方法:在本研究中，我们比较了MMHE和CCHE在最近报道的冷冻保存的人肠细胞中关键的1期氧化和2期结合药物代谢酶(DME)活性:CYP2C9(双氯芬酸4′-羟基化)、CYP2C19 (s-甲苯妥英羟基化)、CYP3A4(咪达唑仑1′-羟基化)、CYP2J2(阿司咪唑o -去甲基化)、尿苷5′-二磷酸葡萄糖醛基转移酶(UGT;7-羟基香豆素葡萄糖醛酸化)，硫转移酶(SULT;7-羟基香豆素磺酸n -乙酰转移酶-1;对苯甲酸n -乙酰化)和羧酶-2 (CES-2;伊立替康水解成SN38)。CCHE和MMHE在所有评估的DME途径中都有活性，MMHE的特异性活性范围为CCHE的142% (CYP2C9)至1713% (UGT)。β-羟基化和睾酮6。结果与结论:MMHE系统是一种方便、可靠的体外药物代谢评价实验系统。

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Drug metabolism letters Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science

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期刊介绍： Drug Metabolism Letters publishes letters and research articles on major advances in all areas of drug metabolism and disposition. The emphasis is on publishing quality papers very rapidly by taking full advantage of the Internet technology both for the submission and review of manuscripts. The journal covers the following areas: In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites.