Perfil clínico de pacientes submetidos à sedação com propofol estratificados por genotipagem de alvos relacionados ao metabolismo do fármaco (UGT1A9, CYP2B6 E CYP2C9)

Abstract

Its success is attributed to its pharmacokinetic properties with fast onset, short duration and minimal side effects. This drug is suitable for induction and maintenance of anesthesia, sedation in intensive care units and outpatient procedures. However, few studies report the impact of genetic polymorphisms on propofol metabolism in different populations, however, always associated with other drugs. In addition, the impact of the c.516G> T (rs3745274), c.98T> C (rs72551330), and c.1075A> C (rs1057910) polymorphisms of the CYP2B6, UGT1A9 and CYP2C9 genes, respectively, on propofol metabolism as a drug unique remains unknown and unprecedented in our population. In this context, the objective of the present study was to associate clinical aspects of patients submitted to sedation with propofol, stratified by genotyping of genes related to the metabolism of the drug in a part of the population of northeastern Brazil. 124 patients were recruited, of both sexes, candidates for colonoscopy under sedation with propofol as a single drug in the Digestive Endoscopy service of Hospital Walter Cantídio-UFC / CE. During the procedure, age, sex, BMI, ASA classification, total dose of propofol, dose of propofol in which he slept, dose of propofol in which he woke up, time of awakening and, every 5 min, hemodynamic variables (HR, PANI) were recorded , SAT O2, TIVA CEF, TCI Plasma and BIS). Peripheral blood samples from patients were allocated to allelic discrimination by quantitative real-time PCR (qPCR). As for the clinical aspects, among all the variables analyzed of the 124 patients submitted to propofol sedation, as a single drug, we found that the patient's gender was the most relevant clinical finding, especially when the concentration of the propofol induction dose was evaluated. Among all the variables analyzed, it was highlighted that the effective concentration of propofol was higher in males (2.77 ± 0.61 µg / mL), when compared to females (2.54 ± 0.52 µg / mL), for the same BIS value (≅ 96, for both sexes) reinforcing the fact that the plasma concentration of propofol depends on factors such as age, body weight, dose, infusion rate, cardiac output and also the patient's sex. It was found that the presence of the polymorphic variant GT and TT of SNP CYP2B6 rs3745274 were associated with lower values of heart rate, systolic and diastolic blood pressure and BIS values when compared to patients with homozygous wild genotype GG, in the evolution process anesthetic and in the evaluation of the different genetic models used. On the other hand, GT and TT patients had higher values of effector TCI, plasma TCI and propofol concentration at awakening (exclusively for patients with TT genotype) when compared to GG patients. It has been suggested that this c.516G> T change correlates with the rate of rapid biotransformation of propofol even when it is administered in a single way, even when analyzing a different population. An important participation of the polymorphic variant C was identified in the heterozygous genotype of the SNP rs1057910 of the CYP2C9 gene, influencing a decrease in the values of TCI Plasma and TIVA CEF, throughout the sedative evolution, being significant more specifically in time T25. In addition, by multivariate analysis, the results presented here demonstrated that the dominant heterozygosis model (wild AA versus heterozygous CA) of this SNP corresponded to a significant predictive factor related to the decrease in the total propofol dose used (B = - 74,161 ± 26,820) . It was concluded that the rs1057910 and rs3745274 polymorphisms affect the metabolism of propofol in patients submitted exclusively to this drug.