Ticlopidine decreases the in vivo activity of CYP2C19 as measured by omeprazole metabolism.
OBJECTIVE
To examine the effect of ticlopidine administration on the activities CYP2C19 and CYP3 A in vivo using omeprazole as a model substrate.


METHODS
A single dose of 40 mg omeprazole was administered orally with or without ticlopidine (300 mg daily for 6 days) to six Japanese extensive metabolisers with respect to CYP2C19. Blood samples were taken for the measurement of plasma concentrations of omeprazole, 5-hydroxyomeprazole and omeprazole sulphone.


RESULTS
Ticlopidine administration increased omeprazole Cmax (1978+/-859/ 3442+/-569 (control phase/ticlopidine phase, nm )) and decreased the oral clearance of omeprazole (CL/F; 25.70+/-16. 17/10.76+/-1.16 (control phase/ticlopidine phase, l h-1 )) significantly. The 5-hydroxyomeprazole to omeprazole AUC ratio (0. 817+/-0.448/0.236+/-0.053 (control phase/ticlopidine phase)) and the 5-hydroxyomeprazole to omeprazole sulphone AUC ratio (1.114+/-0. 782/0.256+/-0.051 (control phase/ticlopidine phase)) were decreased significantly after ticlopidine administration. The decrease in omeprazole CL/F and the 5-hydroxyomeprazole to omeprazole AUC ratio correlated significantly with their respective absolute values when the drug was given alone. The decrease in CL/F following ticlopidine administration correlated with that in the 5-hydroxyomeprazole to omeprazole AUC ratio.


CONCLUSIONS
These findings suggest that ticlopidine inhibited the in vivo activity of CYP2C19, but not, or to a lesser extent CYP3 A4, and that the magnitude of inhibition by ticlopidine is related to the in vivo activity of CYP2C19 before inhibition.
Tateishi
T
T
Department of Pharmacology, St Marianna University School of Medicine, Kanagawa, Japan.
Kumai
T
T
Watanabe
M
M
Nakura
H
H
Tanaka
M
M
Kobayashi
S
S
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009853:Omeprazole / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013988:Ticlopidine / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D010975:Platelet Aggregation Inhibitors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D009853:Omeprazole; D013988:Ticlopidine