title: Relationship of P450 2C9 genetic polymorphisms in Chinese and the pharmacokinetics of tolbutamide.
abstract: 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.
authors.affiliation: Marin Drug & Food Institute, Ocean University of China, Qingdao, China.
authors.forename: K
authors.initials: K
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.forename: S-Y
authors.initials: SY
authors.lastname: Wen
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: S-Q
authors.initials: SQ
authors.lastname: Wang
mesh_terms: 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*
chemical_list: D007004:Hypoglycemic Agents; D014044:Tolbutamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases