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

Abstract

This study was conducted to determine the effect of UGT1A9 98T>C, CYP2B6 516G>T and CYP2C9 430C>T genetic polymorphisms on the pharmacokinetics of propofol in children of different sexes and ages who undergone total intravenous anesthesia (ТIVA) and deep sedation during diagnostic and therapeutic procedures. Patients and Methods: The prospective study included 94 children, ASA I-II status, 1 to 17 years of age, who undergone standard anesthetic protocol for TIVA, which implied the continuous use of propofol. Before the administration of propofol, venous blood was sampled to determine the presence of genetic variations in UGT1A9, CYP2B6 and CYP2C9 gene using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). From each patient included in the study blood samples were taken: 10 mins after the induction of anesthesia, immediately before the discontinuation of the propofol infusion, 10 mins after discontinuation of the propofol infusion and 20 mins after discontinuation of the propofol infusion to determine the pharmacokinetics of the drug in the plasma of the subjects The plasma propofol concentration was determined by HPLC analytical technique. Results: UGT1A9 genotype is an independent predictor of the propofol concentration in children immediately after the end of the continuous infusion and 10 mins afterwards. In the carriers of the polymorphic UGT1A9 C allele, the propofol distribution constant was higher. The carriers of the polymorphic CYP2B6 T allele received a significantly lower overall and initial dose of propofol. Unlike polymorphism of the UGT1A9 gene, the tested CYP2C9 and CYP2B6 gene polymorphisms are not independent predictors of the pharmacokinetics of propofol. Conclusion: Further investigations of UGT1A9, CYP2B6 and CYP2C9 and other genes that participate in propofol metabolism as well as detailed analyses of the general conditions, administered therapies and associated diseases could explain the large interindividual variability of propofol metabolism in children.

GABRA1 and GABRB2 Polymorphisms are Associated with Propofol Susceptibility

“…26 In contrast, some studies have reported that CYP2B6 rs3745274 contributes little to the variation of drug effects of propofol. 3,[27][28][29][30] Our current results suggest that CYP2B6 rs3745274 and rs2279343 do not influence propofol susceptibility during the induction period of anesthesia.…”

Polymorphisms of pharmacogenetic candidate genes affect etomidate anesthesia susceptibility

“…Propofol distribution constant was higher in carriers of the polymorphic UGT1A9 C allele. Carriers of the polymorphic CYP2B6 T allele received significantly lower total and initial doses of propofol ( Pavlovic et al, 2020 ). CYP2C9 (c.1075A>C, rs1057910) was associated with BIS, target-controlled infusion (TCI)/effector concentration of propofol and TCI/plasma concentration of propofol values ( Tong et al, 2021 ); CYP2C9*2 patients required higher propofol concentrations to achieve loss of consciousness (LOC) ( Khan et al, 2014 ).…”

Clinical Importance of Potential Genetic Determinants Affecting Propofol Pharmacokinetics and Pharmacodynamics

“…About 70–90% of propofol is eliminated by urine in the form of the glucuronide metabolite. It is possible that single nucleotide polymorphisms in the genes encoding these enzymes are responsible for the formation of individual variables of propofol metabolic products, resulting in unpredictable effects of standard anesthetic doses as well as prolonged waking time (recovery) from anesthesia ( 25 ).…”

“…The goal of Pavlovic et al ( 25 ) study was to determine how UGT1A9 98T > C, CYP2B6 516G > T, and CYP2C9 430C > T genetic polymorphisms affected propofol pharmacokinetics in children of different sexes and ages who underwent total intravenous anesthesia (TIVA) and deep sedation during diagnostic and therapeutic procedures. This prospective study included 94 children aged 1–17 years old with an ASA I-II status who underwent a conventional anesthetic regimen for TIVA, which included continuous propofol administration.…”