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In vitro metabolism and interaction of cilostazol with human hepatic cytochrome P450 isoforms

Otsuka America Pharmaceutical, Inc., 2440 Research Boulevard, Rockville, Maryland, MD 20850, USA

C P Chow

Department of Drug Safety Evaluation, Purdue Pharma L.P. Ardsley, New York, NY 10502, USA

N J Browder

Otsuka America Pharmaceutical, Inc., 2440 Research Boulevard, Rockville, Maryland, MD 20850, USA

D Thacker

Department of Medicine, The Division of Clinical Pharmacology, Georgetown University Medical Center, Washington, DC, USA

S L Bramer

Otsuka America Pharmaceutical, Inc., 2440 Research Boulevard, Rockville, Maryland, MD 20850, USA

C J Fu

Kansas City Analytical Services, Shawnee, Kansas, KS 66216, USA

W Forbes

Otsuka America Pharmaceutical, Inc., 2440 Research Boulevard, Rockville, Maryland, MD 20850, USA

M Odomi

Tokushima Research Institute, Otsuka Pharmaceutical Company, Tokushima, Japan

D A Flockhart

Department of Medicine, The Division of Clinical Pharmacology, Georgetown University Medical Center, Washington, DC, USA

1. 1 Cilostazol (OPC-13013) undergoes extensive hepatic metabolism. The hydroxylation of the quinone moiety of cilostazol to OPC-13326 was the predominant route in all the liver preparations studies. The hydroxylation of the hexane moiety to OPC-13217 was the second most predominant route in vitro.
   
2. 2 Ketoconazole (1 mM)wasthemostpotentinhibitorof both quinone and hexane hydroxylation. Both the CYP2D6 inhibitor quinidine (0.1 mM) and the CYP2C19 inhibitor omeprazole (10 mM) failed to consistently inhibit metabolism of cilostazol via either of these two predominant routes.
   
3. 3 Data obtained from a bank of pre-characterized human liver microsomes demonstrated a stronger correlation (r²=0.68, P50.01) between metabolism of cilostazol to OPC-13326 and metabolism of felodipine, a CYP3A probe, that with probes for any other isoform. Cimetidine demonstrated concentration-dependent competitive inhibition of the metabolism of cilostazol by both routes.
   
4. 4 Kinetic data demonstrated a Km value of 101 mM for cilostazol, suggesting a relatively low affinity of cilostazol for CYP3A. While recombinant CYP1A2, CYP2D6 and CYP2C19 were also able to catalyze formation of specific cilostazol metabolites, they did not appear to contribute significantly to cilostazol metabolism in whole human liver microsomes.
   

Key Words: cilostazol • in vitro • metabolism • CYP450 • isoforms • interaction

Human & Experimental Toxicology, Vol. 19, No. 3, 178-184 (2000)
DOI: 10.1191/096032700678827717


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