Relationship of P450 2C9 genetic polymorphisms in Chinese and the pharmacokinetics of tolbutamide.
OBJECTIVE
To study the relationship between P450 2C9 genetic polymorphisms and the pharmacokinetics of tolbutamide in Chinese subjects.


METHODS
P450 2C9 genotype was determined by oligonucleotide microarray. Using tolbutamide as a probe of P450 2C9 activity, P450 2C9 phenotype in 20 healthy individuals expressing the P450 2C9*1/*1, *1/*3 and *3/*3 genotypes were evaluated. After administration of 500 mg tolbutamide, plasma and urine samples were collected from each subject over a 24-h period. The tolbutamide and its metabolites' concentrations in human plasma and urine were determined by solid-phase extraction and HPLC.


RESULTS
Tolbutamide AUC0-->infinity increased by 20 and 116%, and T(1/2) increased by 60 and 813%, respectively, in subjects expressing the P4502C9*1/*3 and *3/*3 genotypes compared with *1/*1 subjects. Reductions in tolbutamide oral clearance (68 and 11%) and formation clearance (39 and 3%) were detected in the *1/*3 and *3/*3 individuals, respectively, compared with */*1 subjects.


CONCLUSIONS
The P450 2C9 activity was significantly reduced in *1 heterozygotes compared with *1 homozygotes, and the metabolism of tolbutamide was more severely impaired in *3/*3 individuals compared with those expressing *1/*3. Using tolbutamide as a P450 2C9 probe, P450 2C9 genotype was the major determinant of P450 2C9 phenotype.
Chen
K
K
Marin Drug & Food Institute, Ocean University of China, Qingdao, China.
Wang
R
R
Wen
S-Y
SY
Li
J
J
Wang
S-Q
SQ
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People; D002851:Chromatography, High Pressure Liquid; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic; D014044:Tolbutamide / Q000493:pharmacokinetics*
D007004:Hypoglycemic Agents; D014044:Tolbutamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases