title: CYP2B6 polymorphisms influence the plasma concentration and clearance of the methadone S-enantiomer.
abstract: Methadone is a racemic compound composed of the R-form and S-form enantiomers. The drug is usually used in maintenance therapy for the heroin-addicted patients. In our previous study, we found that the cytochrome P-450 (CYP) isozyme 2B6 preferentially metabolizes the S-methadone enantiomer. We thus tested whether CYP2B6 gene polymorphisms had any influence on the concentration or clearance of methadone. Ten single nucleotide polymorphisms within this gene region were evaluated in 366 patients undergoing methadone maintenance for at least 3 months. The plasma steady-state levels of racemic methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine were then measured in these individuals. The rs10403955 (T allele in intron 1), rs3745274 (G allele in exon 4), rs2279345 (T allele in intron 5), and rs707265 (A allele in exon 9) CYP2B6 allele types were found to be significantly associated with a higher clearance, a lower plasma concentration, and a lower concentration-to-dosage (C/D) ratio of (S)-methadone (P < 0.0017). Two haplotype blocks of a trinucleotide haplotype (rs8100458-rs10500282-rs10403955 in intron 1) and a hexanucleotide haplotype (rs2279342-rs3745274-rs2279343-rs2279345-rs1038376-rs707265 from intron 2 to exon 9) were constructed within CYP2B6. The major combinations of T-T-T and A-G-A-T-A-A of these particular haplotypes showed significant associations with the plasma concentrations of S-methadone and its C/D ratio (P < 0.0001, respectively). We conclude that genetic polymorphisms in the CYP2B6 gene may therefore be indicators of the clearance, plasma concentration and C/D ratio of S-methadone.
authors.affiliation: Division of Mental Health and Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
authors.forename: Sheng-Chang
authors.initials: SC
authors.lastname: Wang
authors.forename: Ing-Kang
authors.initials: IK
authors.lastname: Ho
authors.forename: Hsiao-Hui
authors.initials: HH
authors.lastname: Tsou
authors.forename: Jia-Ni
authors.initials: JN
authors.lastname: Tian
authors.forename: Chin-Fu
authors.initials: CF
authors.lastname: Hsiao
authors.forename: Chia-Hui
authors.initials: CH
authors.lastname: Chen
authors.forename: Happy Kuy-Lok
authors.initials: HK
authors.lastname: Tan
authors.forename: Linen
authors.initials: L
authors.lastname: Lin
authors.forename: Chi-Shin
authors.initials: CS
authors.lastname: Wu
authors.forename: Lien-Wen
authors.initials: LW
authors.lastname: Su
authors.forename: Chieh-Liang
authors.initials: CL
authors.lastname: Huang
authors.forename: Yi-Hong
authors.initials: YH
authors.lastname: Yang
authors.forename: Ming-Lun
authors.initials: ML
authors.lastname: Liu
authors.forename: Keh-Ming
authors.initials: KM
authors.lastname: Lin
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Chen
authors.forename: Shu Chih
authors.initials: SC
authors.lastname: Liu
authors.forename: Hsiao-Yu
authors.initials: HY
authors.lastname: Wu
authors.forename: Hsiu-Wen
authors.initials: HW
authors.lastname: Chan
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Tsai
authors.forename: Pei-Sheng
authors.initials: PS
authors.lastname: Lin
authors.forename: Yu-Li
authors.initials: YL
authors.lastname: Liu
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015331:Cohort Studies; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008691:Methadone / Q000097:blood* / Q000737:chemistry* / Q000493:pharmacokinetics; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013237:Stereoisomerism
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D008691:Methadone