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Biochem Pharmacol. 2015 May 15;95(2):115-25. doi: 10.1016/j.bcp.2015.03.007. Epub 2015 Mar 20.

Influence of HIV antiretrovirals on methadone N-demethylation and transport.

Author information

1
Department of Anesthesiology, Division of Clinical and Translational Research,, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: scott_d_campbell@hotmail.com.
2
Department of Anesthesiology, Division of Clinical and Translational Research,, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: gadels@anest.wustl.edu.
3
Department of Anesthesiology, Division of Clinical and Translational Research,, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: ccfriedel@yahoo.com.
4
Department of Anesthesiology, Division of Clinical and Translational Research,, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: amcrafford13@yahoo.com.
5
Department of Anesthesiology, Division of Clinical and Translational Research,, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: kjjregina@hotmail.com.
6
Department of Anesthesiology, Division of Clinical and Translational Research,, Washington University in St. Louis, St. Louis, MO, USA; Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: kharasch@wustl.edu.

Abstract

Drug interactions involving methadone and/or HIV antiretrovirals can be problematic. Mechanisms whereby antiretrovirals induce clinical methadone clearance are poorly understood. Methadone is N-demethylated to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) by CYP2B6 and CYP3A4 in vitro, but by CYP2B6 in vivo. This investigation evaluated human hepatocytes as a model for methadone induction, and tested the hypothesis that methadone and EDDP are substrates for human drug transporters. Human hepatocyte induction by several antiretrovirals of methadone N-demethylation, and CYP2B6 and CYP3A4 transcription, protein expression and catalytic activity, and pregnane X receptor (PXR) activation were evaluated. Methadone and EDDP uptake and efflux by overexpressed transporters were also determined. Methadone N-demethylation was generally not significantly increased by the antiretrovirals. CYP2B6 mRNA and activity (bupropion N-demethylation) were induced by several antiretrovirals, as were CYP3A4 mRNA and protein expression, but only indinavir increased CYP3A activity (alfentanil dealkylation). CYP upregulation appeared related to PXR activation. Methadone was not a substrate for uptake (OCT1, OCT2, OCT3, OATP1A2, OATP1B1, OATP1B3, OATP2B1) or efflux (P-gp, BCRP) transporters. EDDP was a good substrate for P-gp, BCRP, OCT1, OCT3, OATP1A2, and OATP1B1. OATP1A2- and OCT3-mediated EDDP uptake, and BCRP-mediated EDDP efflux transport, was inhibited by several antiretrovirals. Results show that hepatocyte methadone N-demethylation resembles expressed and liver microsomal metabolism more than clinical metabolism. Compared with clinical studies, hepatocytes underreport induction of methadone metabolism by HIV drugs. Hepatocytes are not a good predictive model for clinical antiretroviral induction of methadone metabolism and not a substitute for clinical studies. EDDP is a transporter substrate, and is susceptible to transporter-mediated interactions.

KEYWORDS:

CYP2B6; CYP3A; Cytochrome P450 2B6; Cytochrome P450 3A; Hepatocytes; Methadone; Protease inhibitors

PMID:
25801005
DOI:
10.1016/j.bcp.2015.03.007
[Indexed for MEDLINE]

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