3,4-Methylenedioxymethamphetamine (MDMA) interacts with therapeutic drugs on CYP3A by inhibition of pregnane X receptor (PXR) activation and catalytic enzyme inhibition

被引：13

作者：

Antolino-Lobo, Irene ^{[1
,2
]}

Meulenbelt, Jan ^{[1
,2
,3
]}

Nijmeijer, Sandra M. ^{[1
]}

Maas-Bakker, Roel F. ^{[4
]}

Meijerman, Irma ^{[4
]}

van den Berg, Martin ^{[1
]}

van Duursen, Majorie B. M. ^{[1
]}

机构：

[1] Univ Utrecht, Inst Risk Assessment Sci, NL-3584 CM Utrecht, Netherlands

[2] Natl Inst Publ Hlth & Environm, Natl Poisons Informat Ctr, NL-3720 BA Bilthoven, Netherlands

[3] Univ Med Ctr Utrecht, Div Intens Care Ctr, Utrecht, Netherlands

[4] Univ Utrecht, Fac Sci, Dept Pharmaceut Sci, Div Biomed Anal, Utrecht, Netherlands

来源：

TOXICOLOGY LETTERS | 2011年 / 203卷 / 01期

关键词：

MDMA; PXR; CYP3A; Sulforaphane; Therapeutic drugs; Drug-drug interactions; NUCLEAR RECEPTOR; CYTOCHROME-P450; 3A4; IN-VITRO; HUMAN HEPATOCYTES; RAT HEPATOCYTES; INDUCTION; ECSTASY; METABOLISM; MECHANISM; SXR;

D O I：

10.1016/j.toxlet.2011.03.007

中图分类号：

R99 [毒物学（毒理学）];

学科分类号：

100405 [卫生毒理学];

摘要：

Metabolism of MDMA (3,4-methylenedioxymethamphetamine, Ecstasy) by the major hepatic drug-metabolizing enzyme cytochrome P450 3A (CYP3A), plays an important role in MDMA-induced liver toxicity. In the present study, we investigated interactions between MDMA and several therapeutic and recreational drugs on CYP3A and its regulator pregnane X receptor (PXR), using a human PXR-mediated CYP3A4-reporter gene assay, rat primary hepatocytes and microsomes. MDMA significantly inhibited hPXR-mediated CYP3A4-reporter gene expression induced by the human PXR activator rifampicin (IC(50) 1.26 +/- 0.36 mM) or the therapeutic drugs paroxetine, fluoxetine, clozapine, diazepam and risperidone. All these drugs concentration-dependently inhibited CYP3A activity in rat liver microsomes, but in combination with MDMA this inhibition became more efficient for clozapine and risperidone. In rat primary hepatocytes that were pretreated with or without the rodent PXR activator pregnenolone 16alpha-carbonitrile (PCN), MDMA inhibited CYP3A catalytic activity with IC(50) values of 0.06 +/- 0.12 and 0.09 +/- 0.13 mM MDMA, respectively. This decrease appeared to be due to decreased activation of PXR and subsequent decreased CYP3A gene expression, and catalytic inhibition of CYP3A activity. These data suggest that in situations of repeated MDMA use in combination with other (therapeutic) drugs, adverse drug-drug interactions through interactions with PXR and/or CYP3A cannot be excluded. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

引用

页码：82 / 91

页数：10

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