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Contribution of CYP2B6 alleles in explaining extreme (S)-methadone plasma levels: a CYP2B6 gene resequencing study

Dobrinas, Maria; Crettol, Séverine; Oneda, Beatrice; Lahyani, Rachel; Rotger, Margalida; Choong, Eva; Lubomirov, Rubin; Csajka, Chantal; Eap, Chin B.

doi: 10.1097/FPC.0b013e32835cb2e2
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Background (S)-Methadone, metabolized mainly by CYP2B6, shows a wide interindividual variability in its pharmacokinetics and pharmacodynamics.

Methods Resequencing of the CYP2B6 gene was performed in 12 and 35 selected individuals with high (S)-methadone plasma exposure and low (S)-methadone plasma exposure, respectively, from a previously described cohort of 276 patients undergoing methadone maintenance treatment. Selected genetic polymorphisms were then analyzed in the complete cohort.

Results The rs35303484 (*11; c136A>G; M46V) polymorphism was overrepresented in the high (S)-methadone level group, whereas the rs3745274 (*9; c516G>T; Q172H), rs2279344 (c822+183G>A), and rs8192719 (c1294+53C>T) polymorphisms were underrepresented in the low (S)-methadone level group, suggesting an association with decreased CYP2B6 activity. Conversely, the rs3211371 (*5; c1459C>T; R487C) polymorphism was overrepresented in the low-level group, indicating an increased CYP2B6 activity. A higher allele frequency was found in the high-level group compared with the low-level group for rs3745274 (*9; c516G>T; Q172H), rs2279343 (*4; c785A>G; K262R) (together representing CYP2B6*6), rs8192719 (c1294+53C>T), and rs2279344 (c822+183G>A), suggesting their involvement in decreased CYP2B6 activity. These results should be replicated in larger independent cohorts.

Conclusion Known genetic polymorphisms in CYP2B6 contribute toward explaining extreme (S)-methadone plasma levels observed in a cohort of patients following methadone maintenance treatment.

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aUnit of Pharmacogenetics and Clinical Psychopharmacology, Department of Psychiatry, Centre for Psychiatric Neurosciences

bInstitute of Microbiology

cDivision of Clinical Pharmacology and Toxicology, University Hospital Center, University of Lausanne, Lausanne

dSchool of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva

eInstitute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland

fDepartment of Clinical Pharmacology, School of Medicine, University Hospital La Paz, Autonomus University of Madrid, Madrid, Spain

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.pharmacogeneticsandgenomics.com).

*Maria Dobrinas and Séverine Crettol contributed equally to the writing of this article.

Correspondence to Chin B. Eap, PhD, Unit of Pharmacogenetics and Clinical Psychopharmacology, Department of Psychiatry, Centre for Psychiatric Neurosciences, Lausanne University Hospital, 1008 Prilly, Lausanne, Switzerland Tel: +41 21 643 64 38; fax: +41 21 643 64 44; e-mail:chin.eap@chuv.ch

Received April 12, 2012

Accepted November 16, 2012

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