Understanding the factors, especially genetic polymorphism, that influence the required personalised dose of propofol in general anaesthesia was the goal of the present study. Justification for our investigation was provided by ambiguous literature data concerning the participation of CYP2B6 and UGT1A9 polymorphisms in propofol metabolism. We have analysed the plasma pharmacokinetic profile of propofol in 85 patients after a stopped infusion of anaesthetic with an average dose of 2.5 mg/kg. As a parameter describing the pharmacokinetics in each patient, the MRT was finally calculated. A high inter-individual variability of the MRT has allowed for the identification of poor, intermediate and rapid metabolisers (Fig. 1).
Analysis of the genotype distribution (for positions c.516 in the CYP2B6, c.98 in the UGT1A9 and c.1075 in the CYP2C9 genes) in all pharmacokinetic profiles showed that only the change c.516G>T correlates with the propofol biotransformation rate. Homozygotes c.516T/T were statistically more often identified in rapid-metabolising individuals.
Our results confirm the significance of this non-synonymous substitution c.516G>T of the CYP2B6 gene in the propofol metabolic rate and further dosing, which was proved in several previous studies (Kansaku et al. 2011; Mastrogianni et al. 2014; Mourão et al. 2016). Kansaku et al. (2011) has proved this change as a genetic factor determining the pharmacokinetics and pharmacodynamics of propofol. They correlated a high maximum blood concentration (Cmax) of anaesthetic with genotype c.516T/T. It may suggest, in contrast to our study, a poor metabolism of propofol. This sequence variation c.516G>T was also the subject of pharmacokinetic research on a group of Greek women. Allele c.516T determined a high blood level of propofol, and its frequency was 29.5% (Mastrogianni et al. 2014). A recent study conducted by Mourão et al. (2016) shared the conclusions formulated by Kansaku et al. (2011) and Mastrogianni et al. (2014), suggesting that allele c.516T determines a lower dose of propofol administered to patients undergoing intravenous general anaesthesia.
On the other hand, Iohom et al. (2007) was the first to suggest an important role of the CYP2B6 gene in the individual pharmacokinetic and pharmacodynamic profiles of propofol. However, they did not demonstrate a correlation between change p.Q172H and clearance of propofol. Similar conclusions were reached in studies performed by Khan et al. (2014); none of the analysed polymorphisms in CYP2B6 were associated with a propofol response. Also, Loryan et al. (2012) did not prove a significant linkage between CYP2B6 and UGT1A9 allelic variants and blood propofol concentration. As they explained, for some of the rare genetic polymorphisms, the study group size was probably too small.
Among the clinical parameters collected in our study, only BMI was significantly correlated with the pharmacokinetic profiles of propofol. A longer retention time observed in patients with higher BMI explains the lipophilic nature of the anaesthetic (Lotia and Bellamy 2008). However, we did not confirm the conclusion propounded by Loryan et al. (2012) concerning the impact of sex on propofol metabolism.
The analysed allele CYP2C9*3 (p.I359L), although it is known as being associated with altered enzyme activity, did not have a significant effect on the biotransformation rate of propofol in our study group. We demonstrated this allele frequency of 4.7 %, which corresponds to the range reported in Caucasians. Global studies proved the allele CYP2C9*3 to be correlated with the overdose risk of warfarin and phenytoin (Lindh et al. 2009). Because, so far, there are no data regarding the role of p.I359L change in the CYP2C9 gene in propofol metabolism in anaesthetised patients, it is difficult to discuss the outcome. Certainly, an important explanation for our results may constitute suggested substrate dependence of the CYP2C9 polymorphism.
The effect of the CYP2B6 p.Q172H change on the propofol pharmacokinetic profile reported in the available studies is not fully elucidated. Nevertheless, CYP2B6 plays an important role in the biotransformation process of this anaesthetic by the hydroxylation pathway. Possibly, in our study group, glucuronidation may be the main reaction in anaesthetic metabolism, which would minimise a significant influence of CYP2B6 gene polymorphism in the propofol response. On the other hand, there are certain differences between parameters in our study and opposed research performed by Kansaku et al. (2011). The average age of patients, as well as the infusion time of propofol, was higher in the Japanese investigation (65 years; an average of 250 min), which may partly explain the significant divergences in the obtained results. Moreover, the analysis time of propofol clearance in our research was limited to the first 30 min after the end of propofol infusion, while in the Japanese study, it reached 60 min. A clearer demonstration of the influence of the CYP2B6 c.516G>T mutation on propofol concentration in patient plasma would probably be possible with the use of the determination of propofol’s metabolites; for example, propofol glucuronide and 4-hydroxypropofol. Additionally, the low frequency of the c.516G>T variant of the CYP2B6 gene may be a source of discrepancies between the studies. Kansaku et al. (2011) found two patients as c.516T homozygotes (of the group of 61 patients) and classified them as poor metabolisers, whereas in our study, three patients were identified as homozygotes TT; however, they were all classified as rapid metabolisers. The statistical analysis has shown the significant correlation of this genotype with a high rate of propofol metabolism.
We can conclude that polymorphism c.516G>T in the CYP2B6 gene and BMI affect the metabolism rate of propofol. Our results constitute an inspiration for further extensive studies including metabolites measurements and larger groups of patients. It is suggested that there are more candidate genes as genetic determinants of individual propofol response, such as genes coding for transporters and receptor proteins (Iohom et al. 2007). By using a valuable tool of molecular biology, high-throughput sequencing techniques, which enable efficient and deep multi-gene analysis, it seems possible to be able to deliver to clinicians the outline for optimal anaesthesia with propofol to avoid the risk of adverse reactions (Pareek et al. 2011).