Lack of differences in diclofenac (a substrate for CYP2C9) pharmacokinetics in healthy volunteers with respect to the single CYP2C9*3 allele.
OBJECTIVE
Evidence exists to suggest that diclofenac is metabolised by CYP2C9. The present study was undertaken in order to evaluate the effect of the single CYP2C9*3 variant on drug metabolism using diclofenac as a probe drug.


METHODS
A single dose of diclofenac was administered orally to 12 healthy subjects in whom the genotype of CYP2C9 had been determined previously. The disposition kinetics of diclofenac were compared between homozygotes for the wild type (CYP2C9*1/*1, n = 6) and heterozygotes for the Leu359 variant (CYP2C9*1/*3, n = 6).


RESULTS
For diclofenac, the following kinetic parameters were observed in the CYP2C9*1/*1 and CYP2C9*1/*3 subjects, respectively (mean +/- SD): apparent oral clearance (ml/kg/h) 355.8 +/- 56.9 and 484.4 +/- 155.3; area under plasma concentration time curve (microg h/ml) 2.7 +/- 0.7 and 1.9 +/- 0.6. The formation clearance of 4'-hydroxydiclofenac (ml/kg/h) was 63.6 +/- 19.1 in the CYP2C9*1/*1 subjects compared with 75.9 +/- 27.6 in the CYP2C9*1/*3 subjects. There were no significant differences in any of the kinetic parameters for either diclofenac disposition or formation clearance of 4'-hydroxydiclofenac between the two genotype groups.


CONCLUSIONS
Since the disposition kinetics of diclofenac does not change in subjects with the single CYP2C9*3 mutant allele, it is suggested that the effects of CYP2C9 polymorphisms on the drug metabolism tend to be substrate specific.
Shimamoto
J
J
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Ieiri
I
I
Urae
A
A
Kimura
M
M
Irie
S
S
Kubota
T
T
Chiba
K
K
Ishizaki
T
T
Otsubo
K
K
Higuchi
S
S
D000328:Adult; D000483:Alleles; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; C108036:4'-hydroxydiclofenac