title: Ethnic and genetic factors in methadone pharmacokinetics: a population pharmacokinetic study.
abstract: BACKGROUND
  Treatment of opiate use disorders with methadone is complicated by wide interindividual variability in pharmacokinetics. To identify potentially contributing covariates in methadone pharmacokinetics, we used population pharmacokinetic modeling to estimate clearance (CL/F) and volume of distribution (V/F) for each methadone enantiomer in an ethnically diverse methadone maintained population.
  
  
  METHODS
  Plasma levels of the opiate-active R-methadone and opiate-inactive S-methadone were measured in 206 methadone maintained subjects approximately two and twenty-three hours after a daily oral dose of rac-methadone. A linear one-compartment population pharmacokinetic model with first-order conditional estimation with interaction (FOCE-I) was used to evaluate methadone CL/F and V/F. The influence of covariates on parameter estimates was evaluated using stepwise covariate modeling. Covariates included ethnicity, gender, weight, BMI, age, methadone dose, and 21 single nucleotide polymorphisms in genes implicated in methadone pharmacokinetics.
  
  
  RESULTS
  In the final model, for each enantiomer, Hmong ethnicity reduced CL/F by approximately 30% and the rs2032582 (ABCB1 2677G>T/A) GG genotype was associated with a 20% reduction in CL/F. The presence of the rs3745274 minor allele (CYP2B6 515G>T) reduced CL/F by up to 20% for S-methadone only. A smaller effect of age was noted on CL/F for R-methadone.
  
  
  CONCLUSIONS
  This is the first report showing the influence of the rs2032582 and rs3745274 variants on methadone pharmacokinetics rather than simply dose requirements or plasma levels. Population pharmacokinetics is a valuable method for identifying the influences on methadone pharmacokinetic variability.
authors.affiliation: Department of Medicine, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN 55415, USA. Electronic address: bartx005@umn.edu.
authors.forename: Gavin
authors.initials: G
authors.lastname: Bart
authors.affiliation: Minneapolis Medical Research Foundation, 914 S 8th St., Minneapolis, MN 55404, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Lenz
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, 5-130 Weaver-Densford Hall, 308 Harvard Street SE, Minneapolis, MN 55455, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Straka
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, 5-130 Weaver-Densford Hall, 308 Harvard Street SE, Minneapolis, MN 55455, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Brundage
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D044466:Asian People / Q000208:ethnology* / Q000235:genetics*; D003430:Cross-Sectional Studies; D005006:Ethnicity / Q000208:ethnology / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008691:Methadone / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D058850:Opiate Substitution Treatment / Q000379:methods; D009293:Opioid-Related Disorders / Q000188:drug therapy / Q000208:ethnology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011159:Population Surveillance / Q000379:methods; D011446:Prospective Studies
chemical_list: D008691:Methadone
keywords: Ethnicity; Genetics; Hmong; Methadone; Pharmacogenetics; Population pharmacokinetics