Longrange PCR-based next-generation sequencing in pharmacokinetics and pharmacodynamics study of propofol among patients under general anaesthesia

Marta Molinska-Glura,Adam Mikstacki,Urszula Lechowicz,Ryszard Slomski,Kinga Huminska-Lisowska,Agnieszka Pollak,Jolanta Dorszewska,Oliwia Zakerska-Banaszak,Barbara Tamowicz,Marzena Skrzypczak-Zielinska,Michal Prendecki,Marlena Szalata,Monika Oldak,Michal Walczak

doi:10.1038/s41598-017-15657-2

Abstract

The individual response of patients to propofol results from the influence of genetic factors. However, the state of knowledge in this matter still remains insufficient. The aim of our study was to determine genetic predictors of variable pharmacokinetics and pharmacodynamics of propofol within selected 9 genes coding for propofol biotransformation enzymes, receptors and transporters. Our studies are the first extensive pharmaocgenetics research of propofol using high throughput sequencing technology. After the design and optimization of long range PCR-based next-generation sequencing experiment, we screened promoter and coding sequences of all genes analyzed among 87 Polish patients undergoing general anaesthesia with propofol. Initially we found that two variants, c.516 G > T in the CYP2B6 gene and c.2677 T > G in the ABCB1 gene, significantly correlate with propofol’s metabolic profile, however after Bonferroni correction the P-values were not statistically significant. Our results suggest, that variants within the CYP2B6 and ABCB1 genes correlate stronger with propofol’s metabolic profile compared to other 7 genes. CYP2B6 and ABCB1 variants can play a potentially important role in response to this anaesthetic and they are promising object for further studies.

Highlights

The individual response of patients to propofol results from the influence of genetic factors
The aim of our study was to identify the genetic determinants of diverse pharmacokinetics and pharmacodynamics of propofol, using deep sequencing of 9 candidate genes including: CYP2C9, CYP2B6, UGT1A9, Sulfotransferase 1A1 (SULT1A1), NAD(P)H quinone dehydrogenase 1 (NQO1), ABCB1, ALB, GABRA1 and ADRA1A
Global studies indicate in particular the contribution of CYP2B6, CYP2C9 and UGT1A9 gene polymorphism to the variability of propofol pharmacokinetics and pharmacodynamics[6,7,8,23]

Summary

Introduction

The individual response of patients to propofol results from the influence of genetic factors. The aim of our study was to determine genetic predictors of variable pharmacokinetics and pharmacodynamics of propofol within selected 9 genes coding for propofol biotransformation enzymes, receptors and transporters. It is known that the biotransformation pathway of propofol includes the action of numerous enzymes, whose polymorphic character may contribute to the individual response of patients to this anaesthetic[2,3]. The greatest contribution to propofol’s individual response is seen in the variants of the CYP2C9, CYP2B6, UGT1A9, SULT1A1, NQO1 genes, involved in the biotransformation pathway of the anaesthestic and of transporting proteins: especially P-glycoprotein and serum albumin, encoded by the ABCB1 and ALB genes, as well as the receptor genes GABRA1 and ADRA1A4,9,10. The substitution p.M33T was proved to determine the pharmacokinetic profile of propofol and the reduced catalytic efficiency of the enzyme[15]

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Conclusion