Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers

Details

Serval ID
serval:BIB_A970376E12E5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers
Journal
Journal of clinical psychopharmacology
Author(s)
Begré S., von Bardeleben U., Ladewig D., Jaquet-Rochat S., Cosendai-Savary L., Golay K.P., Kosel M., Baumann P., Eap C.B.
ISSN
0271-0749
Publication state
Published
Issued date
2002
Peer-reviewed
Oui
Volume
22
Number
2
Pages
211-215
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't - Publication Status: ppublish
Abstract
Steady-state blood concentrations of (R)- methadone (i.e., the active form), (S)-methadone, and (R,S)-methadone were measured before and after introduction of paroxetine 20 mg/day during a mean period of 12 days in 10 addict patients in methadone maintenance treatment. Eight patients were genotyped as CYP2D6 homozygous extensive metabolizers (EMs) and two patients as poor metabolizers (PMs). Paroxetine significantly increased concentrations of both enantiomers of methadone in the whole group (mean increase for (R)-methadone +/- SD, 26 +/- 32%; range, -14% to +83%, p = 0.032; for (S)-methadone, 49 +/- 51%; range, -29% to +137%, p = 0.028; for (R,S)-methadone, 35 +/- 41%; range, -20% to +112%, p = 0.032) and in the group of eight EMs (mean increase, 32%, p = 0.036; 53%, p = 0.028; and 42%, p = 0.036, for (R)-methadone, (S)-methadone, and (R,S)-methadone, respectively). On the other hand, in the two PMs, (S)-methadone but not (R)-methadone concentrations were increased by paroxetine (mean increases of 36% and 3%, respectively). Paroxetine is a strong CYP2D6 inhibitor, and these results confirm previous studies showing an involvement of CYP2D6 in methadone metabolism with a stereoselectivity toward the (R)-enantiomer. Because paroxetine is a mild inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4, increase of (S)-methadone concentrations in both EMs and PMs could be mediated by inhibition of any of these isozymes.
Keywords
Adult, Cytochrome P-450 CYP2D6, Depressive Disorder, Drug Interactions, Drug Therapy, Combination, Female, Humans, Male, Metabolic Clearance Rate, Metabolic Detoxication, Drug, Methadone, Opioid-Related Disorders, Paroxetine
Pubmed
Web of science
Create date
10/03/2008 10:38
Last modification date
20/08/2019 15:13
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