Effect of omeprazole on the metabolism of cilostazol.
OBJECTIVE
In vitro results suggest that cilostazol is metabolised by cytochrome P450 (CYP) isoforms 1A2, 2D6, 3A4 and 2C19. This study was designed to evaluate the effect of concomitant administration of omeprazole (a CYP2C19 inhibitor) on the pharmacokinetics of a single 100 mg oral dose of cilostazol.


METHODS
This study was conducted as a single-centre, open-label, nonrandomised, 2-period, crossover pharmacokinetic trial. A single 100 mg dose of cilostazol was administered orally on days 0 and 14. Oral omeprazole (40 mg every day) was administered on days 7 to 18.


METHODS
20 healthy nonsmoking male and female volunteers.


METHODS
Serial blood samples were collected before and after cilostazol administration to characterise the pharmacokinetics of cilostazol and its metabolites.


RESULTS
Following omeprazole coadministration, the increases in cilostazol maximum plasma concentration (Cmax) and area under the plasma concentration-time curve at time t (AUCt) were 18% (p = 0.062) and 26% (p < 0.001), respectively. For the 2 major circulating metabolites, OPC-13015 and OPC-13213, the OPC-13015 Cmax and AUCt increased by 29 and 69%, respectively (p < 0.001). However, for OPC-13213, the Cmax and AUCt decreased by 22 and 31%, respectively (p < 0.001). The plasma protein binding of cilostazol was unaffected by coadministration of omeprazole.


CONCLUSIONS
Coadministration of cilostazol with omeprazole resulted in an increase in the systemic exposure of cilostazol and its active metabolite, OPC-13015, by 26 and 69%, respectively. For the other active metabolite, OPC-13213, systemic exposure decreased by 31% because of inhibition of cilostazol metabolism to this metabolite. These changes in systemic exposure were well tolerated. A dose of 50 mg cilostazol twice a day should be considered during coadministration of inhibitors of CYP2C19, such as omeprazole.
Suri
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Department of Clinical Pharmacokinetics/Pharmacodynamics & Metabolism, Otsuka America Pharmaceutical, Inc., Rockville, MD 20850, USA. steveb@mocr.oapi.com
Bramer
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D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D000077407:Cilostazol; D018592:Cross-Over Studies; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009853:Omeprazole / Q000494:pharmacology*; D013777:Tetrazoles / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D013777:Tetrazoles; D014665:Vasodilator Agents; D009853:Omeprazole; D000077407:Cilostazol