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Role of Cytochrome P4502B6 in Methadone Metabolism and Clearance
Author(s) -
Kharasch Evan D.,
Stubbert Kristi
Publication year - 2013
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1
Subject(s) - methadone , drug metabolism , metabolic clearance rate , metabolism , pharmacology , cytochrome p450 , cytochrome , medicine , pharmacokinetics , chemistry , drug , biochemistry , enzyme
Methadone N ‐demethylation in vitro is catalyzed by hepatic cytochrome P4502B6 (CYP2B6) and CYP3A4, but clinical disposition is often attributed to CYP3A4. This investigation tested the hypothesis that CYP2B6 is a prominent CYP isoform responsible for clinical methadone N ‐demethylation and clearance, using the in vivo mechanism‐based CYP2B6 inhibitor ticlopidine, given orally for 4 days. A preliminary clinical investigation with the CYP3A4/5 substrate probe alfentanil established that ticlopidine did not inhibit intestinal or hepatic CYP3A4/5. Subjects received intravenous plus oral (deuterium‐labeled) racemic methadone before and after ticlopidine. Ticlopidine significantly and stereoselectively (S > R) inhibited methadone N ‐demethylation, decreasing plasma metabolite/methadone area under the curve ratios and metabolite formation clearances. Ticlopidine also significantly increased the dose‐adjusted plasma area under the curve for R‐ and S‐methadone by 20% and 60%, respectively, after both intravenous and oral dosing. CYP2B6 inhibition reduces methadone N ‐demethylation and clearance, and alters methadone concentrations, demonstrating an important role for CYP2B6 in clinical methadone disposition.