Increased (R)-Methadone Plasma Concentrations by Quetiapine in Cytochrome P450s and ABCB1 Genotyped Patients

Abstract

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.

Methadone: a review of drug-drug and pathophysiological interactions

“…In 14 patients enrolled in MMT, methadone plasma levels were measured before and after introduction of quetiapine (mean dose 138 mg/day, for a mean period of 30 days) 174 . An increase in the (R)-methadone, but not (S)-methadone, concentration to dose ratio was observed.…”

Methadone and methadone metabolites in postmortem specimens

“…CYP 2B6 and 2C19 are polymorphically distributed, resulting in subpopulations of efficient and inefficient metabolizers and substances such as paroxetine and quetiapine have been shown to alter the metabolic rate of methadone [17,18]. Each of these factors, stereoselectivity, polymorphism, and drug interactions, may contribute to rates of methadone demethylation and ultimately to variability in the formation of EMDP.…”

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

“…Some clinical studies have suggested there is a likely relationship (155)(156)(157)(158)(159), while others have suggested there is likely not (161)(162)(163)165), and still others propose that ABCB1 polymorphisms are only one of a number of interacting pharmacogenetic determinants influencing methadone pharmacokinetics (160). Despite extensive research, there remains considerable controversy over the functional consequences of various ABCB1 polymorphisms (222)(223)(224)(225).…”

“…Patients homozygous for the 'T' allele in SNP 1236C>T and carriers of the 3-locus genotype pattern of 'TT-TT-TT' (3435C>T, 2677G>T and 1236C>T polymorphisms) were estimated to have an approximately 7-fold and 5-fold increased chance of requiring higher (>150 mg/day) maintenance methadone doses relative to non-carriers, respectively (156). A Swiss study of 14 MMT subjects found the ABCB1 genotypes 3435 TT, CT, and CC resulted in 3, 23 and 33% increases in (R)-methadone concentration/dose ratios following administration of P-gp substrate quetiapine, respectively (158). Carriers of the variant ABCB1 3435C>T were found to require higher doses of methadone than non-carriers among a population of Han Chinese patients (157), and a pilot study of 178 Taiwanese patients in a MMT program found the ABCB1 2677T allele had positive effects on methadone plasma concentration (159).…”