title: Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance.
abstract: At therapeutic concentrations, cytochrome P4502B6 (CYP2B6) is the major P450 isoform catalyzing hepatic ketamine N-demethylation to norketamine in vitro. The CYP2B6 gene is highly polymorphic. The most common variant allele, CYP2B6*6, is associated with diminished hepatic CYP2B6 expression and catalytic activity compared with wild-type CYP2B6*1/*1. CYP2B6.6, the protein encoded by the CYP2B6*6 allele, and liver microsomes from CYP2B6*6 carriers had diminished ketamine metabolism in vitro. This investigation tested whether humans with the CYP2B6*6 allele would have decreased clinical ketamine metabolism and clearance.
  
  
  
  Thirty volunteers with CYP2B6*1/*1, *1/*6, or *6/*6 genotypes (n = 10 each) received a subsedating dose of oral ketamine. Plasma and urine concentrations of ketamine and the major CYP2B6-dependent metabolites were determined by mass spectrometry. Subjects' self-assessment of ketamine effects were also recorded. The primary outcome was ketamine N-demethylation, measured as the plasma norketamine/ketamine area under the curve ratio. Secondary outcomes included plasma ketamine enantiomer and metabolite area under the plasma concentration-time curve, maximum concentrations, apparent oral clearance, and metabolite formation clearances.
  
  
  
  There was no significant difference between CYP2B6 genotypes in ketamine metabolism or any of the secondary outcome measures. Subjective self-assessment did reveal some differences in energy and level of awareness among subjects.
  
  
  
  These results show that while the CYP2B6*6 polymorphism results in diminished ketamine metabolism in vitro, this allelic variant did not affect single, low-dose ketamine metabolism, clearance, and pharmacokinetics in vivo. While in vitro drug metabolism studies may be informative, clinical investigations in general are needed to validate in vitro observations.
authors.affiliation: From the Division of Clinical and Translational Research, Department of Anesthesiology (L.K.R., A.M.F., C.C.F., E.D.K.), and Department of Biochemistry and Biophysics (E.D.K.), Washington University in St. Louis, St. Louis, Missouri; and the Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University in St. Louis School of Medicine, St. Louis, Missouri (E.D.K.).
authors.forename: Lesley K
authors.initials: LK
authors.lastname: Rao
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Flaker
authors.forename: Christina C
authors.initials: CC
authors.lastname: Friedel
authors.forename: Evan D
authors.initials: ED
authors.lastname: Kharasch
mesh_terms: D000293:Adolescent; D000328:Adult; D000778:Anesthetics, Dissociative / Q000493:pharmacokinetics*; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D005260:Female; D006801:Humans; D007649:Ketamine / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D055815:Young Adult
chemical_list: D000778:Anesthetics, Dissociative; D007649:Ketamine; D065702:Cytochrome P-450 CYP2B6