Abstract
Our previous study detected totally 35 CYP2C9 allelic variants in 2127 Chinese subjects, of whom 21 novel alleles were reported for the first time in Chinese populations. The aim of present study was to characterize the 13 CYP2C9 allelic variants both in vitro and in vivo. Different types of CYP2C9 variants were highly expressed in COS-7 cells and 50 μM of tolbutamide was added as the probing substrate to evaluate their metabolic abilities in vitro. Subsequently, the concentrations of tolbutamide and its metabolite in the plasma and urine within individuals with different types of genotypes were determined by HPLC to evaluate the catalytic activity of the thirteen mutant CYP2C9 proteins in vivo. Our results showed that compared with *1/*1 wild-type subjects, subjects with *1/*40 genotype showed increased oral clearance (CL/F), whereas individuals with*1/*3, *1/*13, *3/*3, *3/*13,*1/*16, *1/*19, *1/*34, *1/*42, *1/*45, *1/*46, and *1/*48 genotype exhibited significantly decreased CL/F, and those with*1/*27, *1/*29, *1/*40 and *1/*41 presented similar CL/F value. When expressed in COS-7 cells, the CYP2C9 variants showed similar pattern to the results in clinical study. The study suggests that besides two typical defective alleles *3 and *13, seven CYP2C9 allelic variants (*16, *19, *34, *42, *45, *46 and *48) cause defective effects on the enzymatic activities both in vitro and in vivo. In clinic, patients with these defective alleles should be paid close attention to.
- cell models
- clinical pharmacology
- cytochrome P450
- in vitro-in vivo prediction (IVIVE)
- pharmacogenetics/pharmacogenomics
- pharmacokinetics
- The American Society for Pharmacology and Experimental Therapeutics