Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance.

Published

Journal Article

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Full Text

Duke Authors

Cited Authors

  • Rao, LK; Flaker, AM; Friedel, CC; Kharasch, ED

Published Date

  • December 2016

Published In

Volume / Issue

  • 125 / 6

Start / End Page

  • 1103 - 1112

PubMed ID

  • 27763887

Pubmed Central ID

  • 27763887

Electronic International Standard Serial Number (EISSN)

  • 1528-1175

Digital Object Identifier (DOI)

  • 10.1097/ALN.0000000000001392

Language

  • eng

Conference Location

  • United States