Effects of CYP3A inhibition on the metabolism of cilostazol.
OBJECTIVE
In vitro results suggest that cilostazol is metabolised by cytochrome P450 (CYP) isoforms 1A2, 2D6, 3A and 2C19. This study investigated the role of CYP3A inhibition on the metabolism of cilostazol.


METHODS
The study was conducted as a single-centre, open-label, nonrandomised, 2-period, crossover pharmacokinetic trial. A single dose of cilostazol 100 mg was administered orally on days 1 and 15. Erythromycin (150 mg orally 3 times daily) was administered on days 8 to 20. 14C-erythromycin (3 microns Ci) was administered intravenously on days 1 and 15 one hour before cilostazol administration to determine baseline and the inhibitory effect of erythromycin treatment on CYP3A activity.


METHODS
16 healthy nonsmoking male volunteers.


METHODS
Serial blood and pooled urine samples were collected before and after cilostazol administration to quantitate cilostazol and its metabolites. Serial exhalation samples were collected after intravenous 14C-erythromycin administration and radioactivity was quantitated by scintillation counting. Pharmacokinetics were determined by noncompartmental methods and compared before and after erythromycin administration. Tolerability assessments included adverse events, laboratory tests, vital signs and electrocardiographs.


RESULTS
Following erythromycin coadministration, cilostazol maximum plasma concentration (Cmax), area under the plasma concentration-time curve at time t (AUCt), and area under the curve from zero to infinity (AUC infinity) increased significantly by 47, 87, and 73%, respectively, and an approximately 50% reduction in unbound clearance was observed for the major circulating metabolite of cilostazol, OPC-13015. Cmax decreased significantly (p < 0.001) by 24%, while AUCt increased by 8%; this increase was not significant. For the second major metabolite, OPC-13213, the Cmax and AUCt increased by 29 and 141%, respectively (p < 0.001).


CONCLUSIONS
In vivo results are in agreement with previous in vitro human microsome studies, indicating that cilostazol is metabolised to OPC-13015 via CYP3A. In addition, OPC-13213 concentrations increased after inhibition of CYP3A because of inhibition of sequential metabolism of OPC-13213 via CYP3A. A starting dose for cilostazol of 50 mg twice daily should be considered during coadministration of inhibitors of CYP3A.
Suri
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Department of Clinical Pharmacokinetics/Pharmacodynamics & Metabolism, Otsuka America Pharmaceutical, Inc., Rockville MD 20850, USA. steveb@mocr.oapi.com
Forbes
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Bramer
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D000284:Administration, Oral; D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D000077407:Cilostazol; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D004917:Erythromycin / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D012044:Regression Analysis; D013777:Tetrazoles / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics
D000900:Anti-Bacterial Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D013777:Tetrazoles; D014665:Vasodilator Agents; D004917:Erythromycin; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000077407:Cilostazol