Lack of influence of CYP2D6 genotype on the clearance of (R)-, (S)- and racemic-methadone.
OBJECTIVE
To investigate the influence of CYP2D6 genotype on the oral clearance of (R)-, (S)- and rac-methadone.


METHODS
In this retrospective study, CYP2D6 genotypes were identified in 56 methadone maintained subjects. Plasma concentrations of (R)-, (S)- and rac-methadone were determined by stereoselective HPLC and sufficient data were available to estimate the apparent oral clearances of (R)-, (S)- and rac-methadone using a population kinetic model in 37 of the genotyped subjects.


RESULTS
The CYP2D6 allele frequencies were similar to those previously reported in Caucasians, the most common being: CYP2D6*1 (35.2%), CYP2D6*2 (12.0%) and CYP2D6*4 (22.2%). Three unknown SNPs were found in four subjects: 1811G > A (n = 1), 1834C > T (n = 1) and 2720G > C (n = 2). The oral clearances of (R)-, (S)- and rac-methadone varied 5.4-, 6.8- and 6.1-fold, respectively. No significant differences in methadone oral clearance were found between CYP2D6 genotypic PM, IM and EM (p = 0.57, 0.40 and 0.43 for (R)-, (S)- and rac-methadone, respectively). Only 1 subject had duplication of functional CYP2D6 alleles and the oral clearance of the three analytes was not markedly altered.


CONCLUSIONS
CYP2D6 poor, intermediate and extensive metabolizer genotypes did not appear to impact on the oral clearance of (R)-, (S)- or rac-methadone. In addition, methadone dosage requirements were not influenced by CYP2D6 genotypes in these subjects. However, the impact of duplication of functional CYP2D6 alleles on oral clearance and dosage requirements requires further investigation.
Coller
J K
JK
Discipline of Pharmacology, Medical School North, University of Adelaide, Australia. janet.coller@adelaide.edu.au
Joergensen
C
C
Foster
D J R
DJ
James
H
H
Gillis
D
D
Christrup
L
L
Somogyi
A A
AA
D000328:Adult; D000483:Alleles; D000701:Analgesics, Opioid / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008691:Methadone / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009293:Opioid-Related Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011247:Pregnancy; D013237:Stereoisomerism
D000701:Analgesics, Opioid; D019389:Cytochrome P-450 CYP2D6; D008691:Methadone