The Effect of UGT1A9, CYP2B6 and CYP2C9 Genes Polymorphism on Propofol Pharmacokinetics in Children

Dimitrije Pavlovic; Ivana Budic; Tatjana Jevtovic Stoimenov; Dragana Stokanovic; Vesna Marjanovic; Marija Stevic; Milan Slavkovic; Dusica Simic

doi:10.2147/PGPM.S231329

The Effect of UGT1A9, CYP2B6 and CYP2C9 Genes Polymorphism on Propofol Pharmacokinetics in Children

Pharmgenomics Pers Med. 2020 Jan 17:13:13-27. doi: 10.2147/PGPM.S231329. eCollection 2020.

Authors

Dimitrije Pavlovic¹, Ivana Budic^{2

3}, Tatjana Jevtovic Stoimenov⁴, Dragana Stokanovic⁵, Vesna Marjanovic^{2

3}, Marija Stevic^{6

7}, Milan Slavkovic⁸, Dusica Simic^{6

7}

Affiliations

¹ Clinic for Plastic and Reconstructive Surgery, Clinical Centre Nis, Nis, Serbia.
² Department of Surgery and Anesthesiology, Faculty of Medicine, University of Nis, Nis, Serbia.
³ Clinic for Anesthesia and Intensive Therapy, Clinical Centre Nis, Nis, Serbia.
⁴ Institute of Biochemistry, Faculty of Medicine, University of Nis, Nis, Serbia.
⁵ Department of Pharmacology and Toxicology, Faculty of Medicine, University of Nis, Nis, Serbia.
⁶ Department of Surgery and Anesthesiology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
⁷ Department of Anesthesiology and Intensive Therapy, University Children's Hospital, Belgrade, Serbia.
⁸ Department of Pediatric Surgery, University Children's Hospital, Belgrade, Serbia.

Abstract

Purpose: 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.

Keywords: children; gene; metabolism; polymorphism; propofol.

Grants and funding

This research was funded by Ministry of Education, Science and Technological Development of the Republic Serbia, grant number III41018.