Effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy subjects

• Published in: Archives of pharmacal research Vol. 46; no. 5; pp. 438 - 447
• Main Authors: Kang, Pureum, Cho, Chang-Keun, Jang, Choon-Gon, Lee, Seok-Yong, Lee, Yun Jeong, Choi, Chang-Ik, Bae, Jung-Woo
• Format: Journal Article
• Language: English
• Published: Seoul Pharmaceutical Society of Korea 01.05.2023; 대한약학회
• Subjects: alleles; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; blood glucose; Cytochrome P-450 CYP2C19 - genetics; Cytochrome P-450 CYP2C9 - genetics; genetic polymorphism; Genotype; Gliclazide - pharmacokinetics; glucose; Healthy Volunteers; Humans; Hypoglycemic Agents - pharmacokinetics; Insulin; Medicine; oral administration; pharmacodynamics; pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Polymorphism, Genetic - genetics; Research Article; 약학; Gliclazide; CYP2C9; Pharmacodynamics; CYP2C19; Pharmacokinetics; Genetic polymorphism
• ISSN: 0253-6269; 1976-3786; 1976-3786
• DOI: 10.1007/s12272-023-01448-z

Gliclazide metabolism is mediated by genetically polymorphic CYP2C9 and CYP2C19 enzymes. We investigated the effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide. Twenty-seven Korean healthy volunteers were administered a single oral dose of gliclazide 80 mg. The plasma concentration of gliclazide was quantified for the pharmacokinetic analysis and plasma concentrations of glucose and insulin were measured as pharmacodynamic parameters. The pharmacokinetics of gliclazide showed a significant difference according to the number of defective alleles of combined CYP2C9 and CYP2C19 . The two defective alleles group (group 3) and one defective allele group (group 2) showed 2.34- and 1.46-fold higher AUC 0–∞ ( P  < 0.001), and 57.1 and 32.3% lower CL/F ( P  < 0.001), compared to those of the no defective allele group (group 1), respectively. The CYP2C9IM– CYP2C19IM group had AUC 0–∞ increase of 1.49-fold ( P  < 0.05) and CL/F decrease by 29.9% ( P  < 0.01), compared with the CYP2C9 Normal Metabolizer ( CYP2C9NM )– CYP2C19IM group. The CYP2C9NM–CYP2C19PM group and CYP2C9NM–CYP2C19IM group showed 2.41- and 1.51-fold higher AUC 0–∞ ( P  < 0.001), and 59.6 and 35.4% lower CL/F ( P  < 0.001), compared to those of the CYP2C9NM–CYP2C19NM group, respectively. The results represented that CYP2C9 and CYP2C19 genetic polymorphisms significantly affected the pharmacokinetics of gliclazide. Although the genetic polymorphism of CYP2C19 had a greater effect on the pharmacokinetics of gliclazide, the genetic polymorphism of CYP2C9 also had a significant effect. On the other hand, plasma glucose and insulin responses to gliclazide were not significantly affected by the CYP2C9–CYP2C19 genotypes, requiring further well-controlled studies with long-term dosing of gliclazide in diabetic patients.