Population pharmacokinetic analysis of glimepiride with CYP2C9 genetic polymorphism in healthy Korean subjects

• Published in: European journal of clinical pharmacology Vol. 67; no. 9; pp. 889 - 898
• Main Authors: Yoo, Hee-Doo, Kim, Mi-Suk, Cho, Hea-Young, Lee, Yong-Bok
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.09.2011; Springer; Springer Nature B.V
• Subjects: Absorption; Administration, Oral; Adult; Aryl Hydrocarbon Hydroxylases - genetics; Asian people; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cross-Over Studies; Cytochrome P-450 CYP2C9; Data processing; Diabetes; Disposition; Gene polymorphism; Genotype & phenotype; Humans; Hypoglycemic Agents - blood; Hypoglycemic Agents - pharmacokinetics; Male; Medical sciences; Metabolic Clearance Rate; Models, Biological; Mouth Mucosa - metabolism; Pharmacogenetics; Pharmacokinetics; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Polymerase Chain Reaction; Polymorphism; Polymorphism, Restriction Fragment Length; Prescription drugs; Republic of Korea; Sulfonylurea Compounds - blood; Sulfonylurea Compounds - pharmacokinetics; Therapeutic Equivalency; Young Adult; Asia; Korea; Republic of Korea; Glimepiride; CYP2C9; Population pharmacokinetics; Genetic polymorphism; Human; Genetic variability; Healthy subject; Enzyme; Isozyme; Cytochrome P450; Genotype; Hypoglycemic agent; Sulfonamides; Sulfonylureas; CYP2C9 gene; Polymorphism
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-011-1035-2

Purpose The purpose of this study was to develop a population pharmacokinetic (PPK) model of glimepiride and to investigate the influence of genetic polymorphisms in CYP2C9 on the PPK of glimepiride in healthy Korean subjects. Methods Serum data after a single oral dose of 2 mg of glimepiride in 177 healthy male Korean subjects ( CYP2C9*1*1 : 163 subjects, *1/*3 : 14 subjects) were used. We estimated the PPK of glimepiride using a nonlinear mixed effects modeling (NONMEM) method and explored the possible influence of genetic polymorphisms in CYP2C9 on the PPK of glimepiride. Results The disposition of glimepiride was best described with a two-compartment model with a Weibull-type absorption and first-order elimination. The visual predictive check indicated that the pharmacokinetic profile of glimepiride was adequately described by the proposed PPK model. The CYP2C9 genotypes as covariate significantly ( P  < 0.001) influenced the apparent oral clearance ( CL/F ) of glimepiride. The estimated CL/F of glimepiride was higher (1.60-fold) in CYP2C9*1/*1 subjects than in CYP2C9*1/*3 subjects. Conclusions This study indicates that genetic polymorphisms of CYP2C9 influence the substantial interindividual variability in the disposition of glimepiride, and these polymorphisms may affect the clinical response to glimepiride therapy.