Influence of sex on propofol metabolism, a pilot study: Implications for propofol anesthesia

Irena Loryan, Marja Lindqvist, Inger Johansson, Masahiro Hiratsuka, Ilse Van Der Heiden, Ron Hn Van Schaik, Jan Jakobsson, Magnus Ingelman-Sundberg

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

Abstract

Purpose 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.

Original languageEnglish
Pages (from-to)397-406
Number of pages10
JournalEuropean Journal of Clinical Pharmacology
Volume68
Issue number4
DOIs
Publication statusPublished - 2012 Apr

Keywords

  • Anesthesia
  • CYP2B6
  • Metabolism
  • Propofol
  • Sex
  • UGT1A9

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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