title: Individual differences in pharmacokinetics and pharmacodynamics of anesthetic agent propofol with regard to CYP2B6 and UGT1A9 genotype and patient age.
abstract: Propofol (2,6-diisopropylphenol) is administered intravenously for induction and maintenance of anesthesia; however, cases of progressive myocardial failure (propofol syndrome) related to the use of propofol have been reported. In the present study, the individual differences in pharmacokinetics and/or pharmacodynamics of propofol were investigated in patients who were genotyped for CYP2B6 and UGT1A9. Fifty-one patients treated with propofol in St. Marianna University Hospital were recruited for this study and provided written informed consent. The following parameters were analyzed: awakening time as a pharmacodynamic parameter, duration of propofol infusion, drug concentration in plasma after treatment, genotypes of CYP2B6 and UGT1A9, and age (42-84 years, mean of 65 years). Propofol was rapidly cleared from the blood of the subjects as a result of distribution and elimination. The awakening time after stopping propofol infusion was significantly correlated with the duration of infusion and the maximum concentration of propofol in these subjects. The maximum plasma concentration of propofol after normalizing with the duration of infusion was affected by the CYP2B6 G516T variant (related to impaired function) and was significantly affected by a propofol risk index score that incorporated CYP2B6 G516T and UGT1A9 I399C>T (high expression) genotypes and advanced age. These results provide important information indicating that the genotypes of the two enzymes studied and advanced age are combinative determinant factors of the pharmacokinetics and/or pharmacodynamics of propofol.
authors.affiliation: Showa Pharmaceutical University, Tokyo, Japan.
authors.forename: Fumiyasu
authors.initials: F
authors.lastname: Kansaku
authors.forename: Toshio
authors.initials: T
authors.lastname: Kumai
authors.forename: Kuniharu
authors.initials: K
authors.lastname: Sasaki
authors.forename: Makito
authors.initials: M
authors.lastname: Yokozuka
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Tadashi
authors.initials: T
authors.lastname: Tateda
authors.forename: Norie
authors.initials: N
authors.lastname: Murayama
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065702:Cytochrome P-450 CYP2B6; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D015742:Propofol / Q000097:blood / Q000493:pharmacokinetics*; D000090264:UDP-Glucuronosyltransferase 1A9
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