CYP2B6 Polymorphisms Influence the Plasma Concentration and Clearance of the Methadone S-Enantiomer
| Autor: | Lien-Wen Su, Keh-Ming Lin, Yi-Hong Yang, Sheng-Chang Wang, Pei-Sheng Lin, Hsiao-Yu Wu, Ming-Lun Liu, Chun-Yu Chen, Chia-Hui Chen, Shu Chih Liu, Chieh-Liang Huang, Hsiu-Wen Chan, Chin-Fu Hsiao, Yu-Li Liu, Ing-Kang Ho, Happy Kuy-Lok Tan, Hsiao-Hui Tsou, Chi-Shin Wu, Jia-Ni Tian, Linen Lin, Ming-Hsien Tsai |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Methadone maintenance CYP2B6 Metabolic Clearance Rate Haplotype Intron Oxidoreductases N-Demethylating Stereoisomerism Single-nucleotide polymorphism Biology Polymorphism Single Nucleotide Molecular biology Isozyme Cohort Studies Cytochrome P-450 CYP2B6 Psychiatry and Mental health Exon Haplotypes Humans Female Pharmacology (medical) Aryl Hydrocarbon Hydroxylases Allele Methadone |
| Zdroj: | Journal of Clinical Psychopharmacology. 31:463-469 |
| ISSN: | 0271-0749 |
| DOI: | 10.1097/jcp.0b013e318222b5dd |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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