Affiliation:
1. From the Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri (E.D.K., K.J.R., J.B., C.F.); and Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, Missouri (E.D.K.).
Abstract
Abstract
Background
Interindividual variability in methadone disposition remains unexplained, and methadone accidental overdose in pain therapy is a significant public health problem. Cytochrome P4502B6 (CYP2B6) is the principle determinant of clinical methadone elimination. The CYP2B6 gene is highly polymorphic, with several variant alleles. CYP2B6.6, the protein encoded by the CYP2B6*6 polymorphism, deficiently catalyzes methadone metabolism in vitro. This investigation determined the influence of CYP2B6*6, and other allelic variants encountered, on methadone concentrations, clearance, and metabolism.
Methods
Healthy volunteers in genotype cohorts CYP2B6*1/*1 (n = 21), CYP2B6*1/*6 (n = 20), and CYP2B6*6/*6 (n = 17), and also CYP2B6*1/*4 (n = 1), CYP2B6*4/*6 (n = 3), and CYP2B6*5/*5 (n = 2) subjects, received single doses of IV and oral methadone. Plasma and urine methadone and metabolite concentrations were determined by tandem mass spectrometry.
Results
Average S-methadone apparent oral clearance was 35 and 45% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1. R-methadone apparent oral clearance was 25 and 35% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1. R- and S-methadone apparent oral clearance was threefold and fourfold greater in CYP2B6*4 carriers. IV and oral R- and S-methadone metabolism was significantly lower in CYP2B6*6 carriers compared with that of CYP2B6*1 homozygotes and greater in CYP2B6*4 carriers. Methadone metabolism and clearance were lower in African Americans in part because of the CYP2B6*6 genetic polymorphism.
Conclusions
CYP2B6 polymorphisms influence methadone plasma concentrations, because of altered methadone metabolism and thus clearance. Genetic influence is greater for oral than IV methadone and S- than R-methadone. CYP2B6 pharmacogenetics explains, in part, interindividual variability in methadone elimination. CYP2B6 genetic effects on methadone metabolism and clearance may identify subjects at risk for methadone toxicity and drug interactions.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Anesthesiology and Pain Medicine
Reference58 articles.
1. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.;J Pain,2009
2. Methadone initiation and rotation in the outpatient setting for patients with cancer pain.;Cancer,2010
3. Intraoperative methadone: Rediscovery, reappraisal, and reinvigoration?;Anesth Analg,2011
4. Integrated prevention services for HIV infection, viral hepatitis, sexually transmitted diseases, and tuberculosis for persons who use drugs illicitly: Summary guidance from CDC and the US Department of Health and Human Services.;MMWR Morb Mortal Wkly Rep,2012
5. Functional inhibition by methadone of N-methyl-D-aspartate receptors expressed in Xenopus oocytes: Stereospecific and subunit effects.;Anesth Analg,2004
Cited by
108 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献