Increased (R)-methadone plasma concentrations by quetiapine in cytochrome P450s and ABCB1 genotyped patients.
Steady-state plasma concentrations of (R)- (ie, the active form), (S)-, and (R,S)-methadone were measured in 14 addict patients in methadone maintenance treatment, before and after introduction of quetiapine, administered at a mean dosage of 138 mg/d (SD, 87 mg/d; median, 125 mg/d; range, 50-300 mg/d) during a mean period of 30 days (SD, 8 days; median, 30 days; range, 20-48 days). Eleven patients were genotyped as being CYP2D6 extensive metabolizers (EMs) and 3 patients as poor metabolizers. Eleven patients had the ABCB1 3435 CT or CC genotypes, and 3 patients had the ABCB1 3435 TT genotype, the latter genotype being associated with lower P-glycoprotein activity. Quetiapine significantly increases (R)-methadone concentration-dose ratios in the whole group [increase for (R)-methadone: mean, +21%; SD, +28%; median, +13%; range, -23% to +85%; P = 0.026], but not for (S)-methadone (mean, +23%; SD, +43%; median, +6%; range, -30% to +115%; P = 0.12) or for (R,S)-methadone (mean, +21%; SD, +34%; median, +9%; range, -21% to +95%; P = 0.064). The mean increases of (R)-methadone concentration-dose ratios were of 7%, 21%, and 30% in the CYP2D6 poor metabolizers, heterozygous EMs, and homozygous EMs, respectively, whereas they were of 3%, 23%, and 33% in the subjects with the ABCB1 3435 TT, CT, and CC genotypes, respectively. Thus, quetiapine increases the plasma concentrations of (R)-methadone, possibly in part by an interaction with CYP2D6 and/or with the P-glycoprotein transporter system. No signs of overmedication caused by increased methadone plasma concentrations were noticed by the staff or reported by the patients.
Uehlinger
Claude
C
Centre Psychosocial, Unité de Traitement des Addictions, Fribourg, Switzerland.
Crettol
Séverine
S
Chassot
Philippe
P
Brocard
Murielle
M
Koeb
Liliane
L
Brawand-Amey
Marlyse
M
Eap
Chin B
CB
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D003987:Dibenzothiazepines / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008691:Methadone / Q000009:adverse effects / Q000097:blood*; D008875:Middle Aged; D009294:Narcotics / Q000009:adverse effects / Q000097:blood*; D009293:Opioid-Related Disorders / Q000534:rehabilitation; D027361:Organic Anion Transporters / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D000069348:Quetiapine Fumarate; D013237:Stereoisomerism
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D007527:Isoenzymes; D009294:Narcotics; D027361:Organic Anion Transporters; D000069348:Quetiapine Fumarate; D003577:Cytochrome P-450 Enzyme System; D008691:Methadone