Pharmacokinetic Drug Interaction between Nifedipine and Gliclazide
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Gliclazide and nifedipine have been clinically prescribed for the prevention or treatment of cardiovascular diseases with diabetes. However, these drugs have potential interaction. The purpose of this study was to investigate the possible effects of gliclazide on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. We evaluated the effect of gliclazide on the activity of P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4. We determined the pharmacokinetic parameters of nifedipine and dehydronifedipine after oral and intravenous administration of nifedipine to rats in the presence or absence of gliclazide (1.0 and 4.0 mg/kg). Gliclazide inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibitory concentration (IC50) of 12.5 μM. The areas under the plasma concentration-time curve (AUC0-∞) and the peak concentration (Cmax) of nifedipine were significantly (4.0 mg/kg, P<0.05) increased by 39.0% and 34.8%, respectively, in the presence of gliclazide, as compare to those of control. In addition, the total body clearance (CL/F) was significantly (4.0 mg/kg, P<0.05) decreased by the treatment with gliclazide (47.9%). Consequently, the absolute bioavailability (AB) of nifedipine in the presence of gliclazide (4.0 mg/kg) was significantly (P<0.05) higher (39.2%) than that of the control group. The metabolite-parent AUC ratio (MR) of nifedipine was significantly decreased by treatment with gliclazide (19.8%). The AUC0-∞ of intravenous nifedipine was significantly (4.0 mg/kg, P<0.05) higher than that of the control group (18.1%), which suggested that gliclazide inhibited the metabolism of nifedipine. The increased bioavailability of nifedipine in the presence of gliclazide may be due to an inhibition of the CYP3A4-mediated metabolism in the small intestine and/or in the liver and gliclazide-mediated reduction of CL/F of nifedipine.
Abstract
Gliclazide and nifedipine have been clinically prescribed for the prevention or treatment of cardiovascular diseases with diabetes. However, these drugs have potential interaction. The purpose of this study was to investigate the possible effects of gliclazide on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. We evaluated the effect of gliclazide on the activity of P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4. We determined the pharmacokinetic parameters of nifedipine and dehydronifedipine after oral and intravenous administration of nifedipine to rats in the presence or absence of gliclazide (1.0 and 4.0 mg/kg). Gliclazide inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibitory concentration (IC50) of 12.5 μM. The areas under the plasma concentration-time curve (AUC0-∞) and the peak concentration (Cmax) of nifedipine were significantly (4.0 mg/kg, P<0.05) increased by 39.0% and 34.8%, respectively, in the presence of gliclazide, as compare to those of control. In addition, the total body clearance (CL/F) was significantly (4.0 mg/kg, P<0.05) decreased by the treatment with gliclazide (47.9%). Consequently, the absolute bioavailability (AB) of nifedipine in the presence of gliclazide (4.0 mg/kg) was significantly (P<0.05) higher (39.2%) than that of the control group. The metabolite-parent AUC ratio (MR) of nifedipine was significantly decreased by treatment with gliclazide (19.8%). The AUC0-∞ of intravenous nifedipine was significantly (4.0 mg/kg, P<0.05) higher than that of the control group (18.1%), which suggested that gliclazide inhibited the metabolism of nifedipine. The increased bioavailability of nifedipine in the presence of gliclazide may be due to an inhibition of the CYP3A4-mediated metabolism in the small intestine and/or in the liver and gliclazide-mediated reduction of CL/F of nifedipine.
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