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.

Effects of Genetic Polymorphism of CYP2B6 and UGT1A9 and Sex Differences on Pharmacokinetics of Propofol

“…The elution profiles of propofol were monitored fluorometrically at an excitation wavelength of 270nm and an emission wavelength of 310 nm. Plasma concentrations of propofol were kinetically analyzed by Phoenix WinNonlin software version 6 (Pharsight, Mountain View, CA, USA) using a two-compartment analysis 15) . We then calculated the half-life of distribution (t 1/2 α) and elimination (t 1/2 β) and the area under the blood concentration-time curve for 60 min (AUC 0-60 ).…”

Effect of sex and polymorphisms of CYP2B6 and UGT1A9 on the difference between the target-controlled infusion predicted and measured plasma propofol concentration

“…The biotransformation of propofol is greatly dependent on liver metabolism [17][18][19], and cytochrome P450 (CYP) 2B6 and uridine diphosphate (UDP)-glucuronosyltransferase (UGT) 1A9, the main enzymes involved in propofol metabolism, are responsible for the hydroxylation and glucuronidation of propofol [20][21][22]. Single-nucleotide polymorphisms (SNPs) in CYP2B6 and UGT1A9 might contribute to the inter-individual variability in the rate of formation of propofol metabolites [21][22][23], while several studies reported no significant effect of these SNPs on propofol metabolism [7,8,10,24].…”

CYP2B6 Genotype Guided Dosing of Propofol Anesthesia in the Elderly Based on Nonparametric Population Pharmacokinetic Modeling and Simulations

“…Several studies have attempted to test whether the polymorphic CYP2B6 gene results in any significant differences in propofol clearance and consciousness following bolus doses and infusions, but none have resulted in recommendations for gene-guided propofol dosage adjustments [8,[10][11][12][13].…”