Effects of Baicalein on the Bioavailability of Nicardipine in Rats

Abstract

This study was to investigate the effect of baicalein, an antioxidant, on the bioavailability of nicardipine after orally or intravenously administered nicardipine in rats. Nicardipine was administered orally (12 mg/kg) or intra- venously (4 mg/kg) with or without orally administered baicalein (0.4, 2 or 10 mg/kg) to rats. In the inhibitory effect of baicalein on CYP3A4 activity, baicalein inhibited CYP3A4 activity with IC50 values of 9.2 µM. The cell-based P-gp activity test using rhodamine-123 also showed that baicalein (30-10 µM, p<0.01) significantly inhibited P-gp activity. Compared with the control group (given nicardipine alone), the area under the plasma concentration-time curve (AUC) was sig- nificantly (2 mg/kg, P<0.05; 10 mg/kg, P<0.01) increased by 25.9-60.0%, and the peak concentration (Cmax) was sig- nificantly (10 mg/kg, P<0.01) increased by 40.0% in the presence of baicalein after orally administration of nicardipine. Consequently, the relative bioavailability (R.B.) of nicardipine was increased by 1.26- to 1.60-fold and the absolute bio- availability (A.B.) was significantly (2 mg/kg, P<0.05; 10 mg/kg, P<0.01) increased by 26.0-59.9%. Compared to the i.v. control, baicalein did not significantly change pharmacokinetic parameters of nicardipine in i.v. administration. Accordingly, the enhanced oral bioavailability of nicardipine might be mainly due to increased intestinal absorption caused by P-gp inhi- bition rather than to reduced elimination of nicardipine by baicalein. The increase in the oral bioavailability might be mainly attributed to enhanced absorption in the small intestine via the inhibition of P-gp and reduced first-pass metabolism of nica- rdipine via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver by baicalein. Based on these results, nicardipine dosage should be adjusted when given concomitantly with baicalein. Key wordsNicardipine, Baicalein, CYP3A4, P-gp, Bioavailability, Pharmacokinetics, Rats Nicardipine, a dihydropyridine calcium channel antagonist, causes coronary and peripheral vasodilatation by blocking the influx of extracellular calcium across cell membranes. Nica- rdipine is arterioselective and effective for the treatment of