Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers.
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.
Begré
Stefan
S
Psychiatrische Universitätsklinik Basel, Basel, Switzerland.
von Bardeleben
Ulrich
U
Ladewig
Dieter
D
Jaquet-Rochat
Sylvie
S
Cosendai-Savary
Line
L
Golay
Kerry Powell
KP
Kosel
Markus
M
Baumann
Pierre
P
Eap
Chin B
CB
D000328:Adult; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003866:Depressive Disorder / Q000097:blood / Q000523:psychology / Q000534:rehabilitation*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008691:Methadone / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D009293:Opioid-Related Disorders / Q000097:blood / Q000523:psychology / Q000534:rehabilitation*; D017374:Paroxetine / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D017374:Paroxetine; D008691:Methadone