Impact of genetic variations on the pharmacokinetics, dose requirements, and clinical effects of propofol: a systematic review

Abstract

Introduction: Both the dose requirements and side-effects of propofol vary significantly between individuals. Propofol is primarily metabolised by uridine 5'-diphosphate-glucuronosyltransferase (UGT) and cytochrome P450 (CYP) enzymatic pathways, specifically UGT1A9 (70%) and CYP2B6/CYP2C9 (29%). Genetic polymorphisms, which influence enzyme transcription and function, can influence propofol metabolism and propofol clearance and thereby potentially impact anaesthesia-related clinical outcomes. Pharmacogenomic testing can assist with individualising propofol dosing during total intravenous anaesthesia (TIVA) to improve safety and efficacy. This systematic review evaluates the impact of metabolic genetic polymorphisms on propofol clearance, dose requirements, and related clinical effects.

Methods: A systematic search of MEDLINE, EMBASE, and the Pharmacogenomics Knowledge Base identified studies involving patients who underwent propofol-based TIVA and pharmacogenomic testing for UGT1A9, CYP2B6, and CYP2C9 genotypes.

Results: Sixteen studies, involving 1779 patients receiving propofol-TIVA, were included. Of the UGT1A9 polymorphism genotypes considered, CT heterozygotes of rs72551330 (98T>C) may have a clinically relevant effect on propofol pharmacokinetics, with lower propofol clearance, lower dose requirements, and longer emergence times. CC homozygotes of rs2741045 (-440C>T) may have higher propofol clearance with faster emergence. Given currently available data, the CYP2B6 and CYP2C9 genotypes do not appear to have significant influence on propofol pharmacokinetics or anaesthesia-related clinical outcomes.

Conclusions: Genetic polymorphisms in propofol metabolism can influence the pharmacokinetics of propofol and, potentially, anaesthesia-related clinical outcomes. To confirm these observations, larger, well-designed pharmacokinetic studies exploring metabolic genetic polymorphisms as covariates are required. Such data could support pharmacogenomic-guided propofol dosing.

Keywords: genetics; personalised anaesthesia; pharmacogenomics; pharmacokinetics; propofol; total i.v. anaesthesia.