[Impact of cytochrome P450 CYP2C9 variant allele CYP2C9 * 3 on the pharmacokinetics of glibenclamide and lornoxicam in Chinese subjects].
OBJECTIVE
To investigate the impact of CYP2C9 * 3 on the pharmacokinetics of glibenclamide and lornoxicam.


METHODS
CYP2C9 * 3 was measured in 83 non-related Chinese subjects by PCR-RFLP. The pharmacokinetics of lornoxicam and glibenclamide were investigated in 18 subjects (7 with CYP2C9 * 1/* 3 genotype and 11 with * 1/* 1 genotype). Glibenclamide and lornoxicam in plasma were determined by the sensitive liquid chromatography-tandem mass spectrometry, separately.


RESULTS
After a single oral dose of 2.5 mg glibenclamide, C(max) was (70.0 +/- 11.5) microg x L(-1) in CYP2C9 * 1/ * 3 subjects and (51.9 +/- 12.3) microg x L(-1) in * 1/ *1 subjects. AUC(0-infinity) were (435 +/- 47) vs (287 +/- 95) microg x h x L(-1) (in * 1/ * 3 vs * 1/ *1 subjects), and CL/F were (96 +/- 9.3) vs (160 +/- 51) mL x min(-1), respectively. Statistic analysis results indicated that glibenclamide AUC(0-infinity) was significantly higher (1.5-fold) and subsequently CL/F was significantly lower (40%) in CYP2C9 * 1/ * 3 subjects than those in * 1/ * 1 subjects (P < 0.01). After a single oral dose of 8 mg lornoxicam, C(max) was (1.54 +/- 0.24) mg x L(-1) in CYP2C9 * 1/ * 3 subjects and (1.19 +/- 0.37) mg x L(-1) in * 1/ * 1 subjects. AUC(o-infinity were (14.9 +/- 2.2) vs (6.92 +/- 1.48) mg x h x L(-1) (in * 1/ *3 vs * 1/ * 1 subjects), and CL/F were (9.1 +/- 1.2) vs (20.1 +/- 4.6) mL x min(-1), respectively. Statistic analysis results indicated that lornoxicam AUC(0-infinity) was significantly higher (2. 2-fold) and subsequently CL/F was significantly lower (55% ) in CYP2C9 * 1/ * 3 subjects than those in * 1/ * 1 subjects (P < 0.001).


CONCLUSIONS
CYP2C9 * 3 greatly affects both the pharmacokinetic profiles of glibenclamide and lornoxicam. The elimination of these drugs significantly decreased in subjects with CYP2C9 * 1/ * 3 genotype, especially lornoxicam.
Zhang
Yi-Fan
YF
Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, Shenyang 110016, China.
Chen
Xiao-Yan
XY
Guo
Ying-Jie
YJ
Si
Da-Yong
DY
Zhou
Hui
H
Zhong
Da-Fang
DF
D000328:Adult; D000483:Alleles; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People; D002681:China; D065729:Cytochrome P-450 CYP2C9; D005838:Genotype; D005905:Glyburide / Q000493:pharmacokinetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics; D008297:Male; D010894:Piroxicam / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007004:Hypoglycemic Agents; D010894:Piroxicam; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C059451:lornoxicam; D005905:Glyburide