title: Influence of sex on propofol metabolism, a pilot study: implications for propofol anesthesia.
abstract: OBJECTIVE
  The basis of high intersubject variability of propofol metabolism is unclear. Therefore, we examined the influence of genetic polymorphisms of the key metabolizing enzymes cytochrome P450 2B6 (CYP2B6) and uridine diphosphate (UDP)-glucuronosyltransferase 1A9 (UGT1A9), age, and sex on propofol biotransformation in vitro and in vivo.
  
  
  METHODS
  Plasma concentrations of propofol, 4-hydroxypropofol, and their glucuronides were measured over 20 min in 105 patients after a single intravenous bolus of propofol. Propofol 4-hydroxylation activity, genotypes, and content of CYP2B6 protein in 68 human livers were determined. The common single nucleotide polymorphisms (SNPs) for the CYP2B6 and UGT1A9 genes were analyzed by polymerase chain reaction (PCR).
  
  
  RESULTS
  Plasma levels of propofol metabolites showed high interindividual variability (range of coefficient of variation 89-128%). This was supported by in vitro data showing similar variability of propofol 4-hydroxylation in liver microsomes and 1.9-fold higher CYP2B6 protein content in the livers from women. No significant relationships were revealed between the SNPs studied and propofol metabolism. However, patients' sex had a pronounced effect on propofol metabolism. Thus, women had higher amounts of propofol glucuronide (1.25-fold; p = 0.03), 4-hydroxypropofol-1-glucuronide (2.1-fold; p = 0.0009), and 4-hydroxypropofol-4-glucuronide (1.7-fold; p = 0.02) as shown by the weight-corrected area under the time-plasma concentration curve of metabolites. Additionally, the sexual dimorphism in 4-hydroxypropofol glucuronidation was prominent in the 35- to 64-year-old subgroup.
  
  
  CONCLUSIONS
  No significant effects of CYP2B6 and UGT1A9 SNPs or age on propofol metabolism were revealed in this pilot study, but there was a pronounced effect of sex, a finding that indicates an important factor for the previously described sex difference in systemic clearance of propofol seen.
authors: Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
authors: Irena
authors: I
authors: Loryan
authors: Marja
authors: M
authors: Lindqvist
authors: Inger
authors: I
authors: Johansson
authors: Masahiro
authors: M
authors: Hiratsuka
authors: Ilse
authors: I
authors: van der Heiden
authors: Ron H N
authors: RH
authors: van Schaik
authors: Jan
authors: J
authors: Jakobsson
authors: Magnus
authors: M
authors: Ingelman-Sundberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018686:Anesthetics, Intravenous / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D015742:Propofol / Q000097:blood / Q000493:pharmacokinetics*; D012737:Sex Factors; D000090264:UDP-Glucuronosyltransferase 1A9; D055815:Young Adult
chemical_list: D018686:Anesthetics, Intravenous; C000715591:UGT1A9 protein, human; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; D015742:Propofol