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|Title:||Lack of influence of CYP2D6 genotype on the clearance of (R)- (S)- and racemic-methadon|
|Citation:||International Journal of Clinical Pharmacology and Therapeutics, 2007; 45(7):410-417|
|Publisher:||Dustri-Verlag Dr Karl Feistle|
|J.K. Coller, C. Joergensen, D.J.R. Foster, H. James, D. Gillis, L. Christrup and A.A. Somogyi|
|Abstract:||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.|
|Keywords:||Humans; Pain; Opioid-Related Disorders; Methadone; Cytochrome P-450 CYP2D6; Analgesics, Opioid; Pregnancy; Genotype; Phenotype; Alleles; Stereoisomerism; Adult; Female; Male|
|Appears in Collections:||Pharmacology publications|
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