ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment

Crettol, Séverine; Déglon, Jean-Jacques; Besson, Jacques; Croquette-Krokar, Marina; Hämmig, Robert; Gothuey, Isabelle; Monnat, Martine; Eap, Chin B (2006). ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment. Clinical pharmacology & therapeutics, 80(6), pp. 668-81. New York, N.Y.: Nature Publishing Group 10.1016/j.clpt.2006.09.012

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BACKGROUND AND OBJECTIVE: The in vivo implication of various cytochrome P450 (CYP) isoforms and of P-glycoprotein on methadone kinetics is unclear. We aimed to thoroughly examine the genetic factors influencing methadone kinetics and response to treatment. METHODS: Genotyping for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, and UGT2B7 polymorphisms was performed in 245 patients undergoing methadone maintenance treatment. To assess CYP3A activity, the patients were phenotyped with midazolam. RESULTS: The patients with lower CYP3A activity presented higher steady-state trough (R,S)-methadone plasma levels (4.3, 3.0, and 2.3 ng/mL x mg for low, medium, and high activity, respectively; P = .0002). As previously reported, CYP2B6*6/*6 carriers had significantly higher trough (S)-methadone plasma levels (P = .0001) and a trend toward higher (R)-methadone plasma levels (P = .07). CYP2D6 ultrarapid metabolizers presented lower trough (R,S)-methadone plasma levels compared with the extensive or intermediate metabolizers (2.4 and 3.3 ng/mL x mg, respectively; P = .04), whereas CYP2D6 poor metabolizer status showed no influence. ABCB1 3435TT carriers presented lower trough (R,S)-methadone plasma levels (2.7 and 3.4 ng/mL . mg for 3435TT and 3435CC carriers, respectively; P = .01). The CYP1A2, CYP2C9, CYP2C19, CYP3A5, and UGT2B7 genotypes did not influence methadone plasma levels. Only CYP2B6 displayed a stereoselectivity in its activity. CONCLUSION: In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > University Psychiatric Services > University Hospital of Psychiatry and Psychotherapy > UPD Murtenstrasse

UniBE Contributor:

Hämmig, Robert

ISSN:

0009-9236

ISBN:

17178267

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:51

Last Modified:

06 Dec 2013 13:44

Publisher DOI:

10.1016/j.clpt.2006.09.012

PubMed ID:

17178267

Web of Science ID:

000243086700011

URI:

https://boris.unibe.ch/id/eprint/21767 (FactScience: 13621)

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