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

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.

Metabolic Profiles of Propofol and Fospropofol: Clinical and Forensic Interpretative Aspects

“…Moreover, propofol was likely to be metabolized by additional isoforms such as CYP2A6, CYP2C8, CYP2C18, CYP2C19, and CYP1A2, especially when substrate concentrations are high [ 95 ]. From a clinical perspective, this low specificity among CYP isoforms may contribute to a low interindividual variability and reduced metabolic drug interactions [ 95 ], but opposite results have been observed [ 97 ]. Indeed, in spite of its low (1–5%) contribution to the total liver CYP content, CYP2B6 polymorphisms also have a significant impact on the CYP2B6-dependent metabolism of several clinically relevant drugs such as cyclophosphamide, S -methadone, efavirenz, nevirapine, bupropion, selegiline, and propofol [ 98 , 99 ].…”

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

“…In a retrospective analysis of 17,540 patients, with 4033 being over the age of 65 years, patients over 70 years of age experienced a dose-dependent increases in hypotension [21]. Further, a study by Mikstacki and colleagues recently reported that the CYP2B6 gene and patients' body mass index were associated with propofol metabolic rates and optimizing of propofol anesthesia [22].…”

<p>The Effect of <em>UGT1A9</em>, <em>CYP2B6</em> and <em>CYP2C9</em> Genes Polymorphism on Propofol Pharmacokinetics in Children</p>

“…HPLC analytical techniques were applied to measure the content of propofol in plasma, based on the methods described by Moghaddam et al 7 and Mikstacki et al 2 For analysis, 200 μL of plasma was used, which was first deproteined with 200 μL of trifluoroacetic acid (TFA) solution in acetonitrile (0.3%). After a short vortex, centrifugation was followed at 12,000 rpm for 10 min at 4°C.…”

“…Propofol is mainly metabolized by hepatic and extrahepatic cytochrome P450 2B6 (CYP2B6) and cytochrome P450 2C9 (CYP2C9), 2 as well as by UDP-glucuronosulfotransferase 1A9 (UGT1A9). UDP-glucuronosulfotransferase 1A9 (UGT1A9) catalyzes the formation of propofol glucuronide.…”