Effects of Cilostazol on the Pharmacokinetics of Nifedipine After Oral and Intravenous Administration in Rats

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The purpose of this study was to investigate the effects of cilostazol on the bioavailability and pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The pharmacokinetic parameters of nifedipine and dehydronifedipine were determined following oral and intravenous administration of nifedipine (1.5 and 6.0 mg ・ kg^-1) in rats. Cilostazol inhibited CYP3A4 enzyme activity at a 50% inhibitory concentration (IC₅₀) of 4.1 μM. The areas under the plasma concentration–time curve (AUC_0-∞) and the peak concentration (C_max) of nifedipine were significantly increased, respectively, in the presence of cilostazol compared to that in the control. The total body clearance (CL/F) was significantly decreased by cilostazol. Consequently, the absolute bioavailability (AB) of nifedipine with cilostazol was significantly higher than that in the control. The metabolite to parent AUC ratio (MR) in the presence of cilostazol was significantly decreased compared to that in the control. The AUC_0-∞ of intravenous nifedipine was significantly increased with cilostazol compared to that in the control. The increased bioavailability of nifedipine in rats can be mainly due to the inhibition of CYP3A4-mediated metabolism in the small intestine and/or liver by cilostazol. In addition, the reduction of CL/F of nifedipine by cilostazol may also be a factor.