No major difference in inhibitory susceptibility between CYP2C9.1 and CYP2C9.3.
OBJECTIVE
CYP2C9 is a polymorphic enzyme, and CYP2C9*3 is associated with decreased metabolic activity. In addition to the impaired metabolism, we investigated whether the CYP2C9*3 exhibited altered inhibitory susceptibility compared with CYP2C9*1.


METHODS
In the present study, CYP2C9.1 and CYP2C9.3 were expressed in yeast. Using typical CYP2C9 substrates (diclofenac, tolbutamide and S-warfarin) and a potent CYP2C9 inhibitor (nicardipine), the Ki values for nicardipine on the three metabolisms in CYP2C9*1 and CYP2C9*3 were determined.


RESULTS
The ratios of Ki(CYP2C9*3)/Ki(CYP2C9*1) on tolbutamide, diclofenac and S-warfarin metabolisms were 1.2, 3.1 and 0.8, respectively.


CONCLUSIONS
In conclusion, there are no significant differences in the inhibitory susceptibility between the two CYP2C9 enzymes.
Hanatani
Tadaaki
T
Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
Fukuda
Tsuyoshi
T
Onishi
Sachi
S
Funae
Yoshihiko
Y
Azuma
Junichi
J
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D004008:Diclofenac / Q000378:metabolism; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009529:Nicardipine / Q000494:pharmacology; D011110:Polymorphism, Genetic; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D014044:Tolbutamide / Q000378:metabolism; D014859:Warfarin / Q000378:metabolism
D004008:Diclofenac; D014859:Warfarin; D014044:Tolbutamide; D009529:Nicardipine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases