The effect of UGT1A9, CYP2B6 and CYP2C9 genes polymorphism on individual differences in propofol pharmacokinetics among Polish patients undergoing general anaesthesia

Adam Mikstacki,Jolanta Dorszewska,Marta Molinska-Glura,Oliwia Zakerska-Banaszak,Ryszard Slomski,Malgorzata Waszak,Michał Prendecki,Marzena Skrzypczak-Zielinska,Barbara Tamowicz

doi:10.1007/s13353-016-0373-2

Abstract

Propofol (2,6-diisopropylphenol) is one of the safest and most commonly used anaesthetic agents for intravenous general anaesthesia. However, in clinical practice, a large inter-individual variability in response to propofol is observed. To limit the risk of adverse effects, pharmacogenetic investigations are recommended. The aim of our study was to verify the impact of genetic changes c.516G>T in the CYP2B6, c.98T>C in the UGT1A9 and c.1075A>C in the CYP2C9 genes on the individual propofol pharmacokinetic profile in the Polish patients undergoing general anaesthesia. Eighty-five patients from the Department of Anaesthesiology and Intensive Therapy, Regional Hospital in Poznan, Poland, anaesthetised with propofol for surgery, were enrolled in the study. We have genotyped CYP2B6, UGT1A9 and CYP2C9 polymorphisms with the use of pyrosequencing. HPLC measurements of propofol plasma concentration were applied for a pharmacokinetic analysis of the anaesthetic. We identified poor (20), intermediate (42) and rapid (23) metabolisers of propofol, which constituted 24%, 49% and 27% of the group, respectively. Homozygotes c.516 T/T in the CYP2B6 gene were statistically more often found in the rapid metabolisers group (p < 0.05). However, polymorphisms c.98T>C in the UGT1A9 and c.1075A>C in the CYP2C9 genes did not affect the pharmacokinetic profile of propofol. The mean propofol retention time (MRT) correlated with the patient’s body mass index (BMI) (p < 0.05). From all the analysed changes, only polymorphism c.516G>T in the CYP2B6 gene and BMI affect the metabolism rate of propofol and may play an important role in the optimisation of propofol anaesthesia.

Highlights

Propofol is one of the safest and most commonly used anaesthetic agents for intravenous general anaesthesia
A total of 85 individuals were successfully screened for genetic variants p.Q172H (c.516G>T) in the cytochrome P450 2B6 (CYP2B6), p.M33T (c.98T>C) in the UDP-glucuronosyltransferase 1A9 (UGT1A9) and p.I359L (c.1075A>C) in the cytochrome P450 2C9 (CYP2C9) genes, using pyrosequencing
The results showed that allele CYP2B6*9 (c.516T) was present in the study group with a frequency of 18 %, while the frequencies of alleles UGT1A9*3 (c.98C) and CYP2C9*3 (c.1075C) were 2% and 4.7%, respectively

Summary

Introduction

Propofol is one of the safest and most commonly used anaesthetic agents for intravenous general anaesthesia. In clinical practice, a large inter-individual variability, including adverse reactions, is observed in response to this anaesthetic (Pasin et al 2015). Changes between individuals in the pharmacokinetics of propofol result in differences in the required dose of anaesthetic needed for efficient general anaesthesia (Karwacki et al 2014). This variability is mostly assigned to the genetic polymorphism of genes coding for enzymes participating in the biotransformation pathway of propofol (Kübler 2005; Mikstacki et al 2013). The need for gene profiling in anaesthesia has been suggested many times recently (Landau et al 2012).

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