In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics.
In-vitro studies were conducted to assess the impact of CYP2C9 genotype on the metabolism (methyl hydroxylation) and pharmacokinetics of celecoxib, a novel cyclooxygenase-2 inhibitor and CYP2C9 substrate. When compared to cDNA-expressed wild-type CYP2C9 (CYP2C9*1), the Vmax/Km ratio for celecoxib methyl hydroxylation was reduced by 34% and 90% in the presence of recombinant CYP2C9*2 and CYP2C9*3, respectively. These data indicated that the amino acid substitution at position 359 (Ile to Leu) elicited a more pronounced effect on the metabolism of celecoxib than did a substitution at position 144 (Arg to Cys). The Vmax/Km ratio was also decreased in microsomes of livers genotyped CYP2C9*1/*2 (47% decrease, mean of two livers), or CYP2C9*1/*3 (59% decrease, one liver). In all cases, these changes were largely reflective of a decrease in Vmax, with a minimal change in Km. Based on simulations of the in-vitro data obtained with the recombinant CYP2C9 proteins, it was anticipated that the pharmacokinetics of celecoxib (as a much as a five-fold increase in plasma AUC) would be altered (versus CYP2C9*1/*1 subjects) in subjects genotyped heterozygous or homozygous for the CYP2C9*2 (Cys144) or CYP2C9*3 (Leu359) allele. In a subsequent clinical study, the AUC of celecoxib was increased (versus CYP2C9*1/*1 subjects) approximately 2.2-fold (range, 1.6-3-fold) in two CYP2C9*1/*3 subjects and one CYP2C9*3/*3 subject receiving a single oral dose (200 mg) of the drug. In contrast, there was no significant change in celecoxib AUC in two subjects genotyped CYP2C9*1/*2.
Tang
C
C
Drug Metabolism, Merck Research Laboratories, West Point, PA, USA. cuyue_tang@merck.com
Shou
M
M
Rushmore
T H
TH
Mei
Q
Q
Sandhu
P
P
Woolf
E J
EJ
Rose
M J
MJ
Gelmann
A
A
Greenberg
H E
HE
De Lepeleire
I
I
Van Hecken
A
A
De Schepper
P J
PJ
Ebel
D L
DL
Schwartz
J I
JI
Rodrigues
A D
AD
D000284:Administration, Oral; D000328:Adult; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics*; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D017931:DNA Primers / Q000737:chemistry; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics*; D013449:Sulfonamides / Q000493:pharmacokinetics*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D017931:DNA Primers; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; 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; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib