Effects of Kaempferol, an Antioxidant, on the Bioavailability and Pharmacokinetics of Nimodipine in Rats

Abstract

The aim of this study was to investigate the effects of kaempferol on the pharmacokinetics of nimodipine in rats. Nimodipine and kaempferol interact with cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), and the increase in the use of health supplements may result in kaempferol being taken concomitantly with nimodipine as a combination therapy to treat orprevent cardiovascular disease. The effect of kaempferol on P-gp and CYP3A4 activity was evaluated and Pharmacokinetic parameters of nimodipine were determined in rats after an oral (12 mg/kg) and intravenous (3 mg/kg) administration of nimodipine to rats in the presence and absence of kaempferol (0.5, 2.5, and 10 mg/kg). Kaempferol inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration (IC50) of 17.1 µM. In addition, kaempferol significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ ADR cells overexpressing P-gp. Compared to the oral control group, the area under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (Cmax) of nimodipine significantly increased, respectively. Consequently, the absolute bioavailability of nimodipine in the presence of kaempferol (2.5 and 10 mg/kg) was 29.1-33.3%, which was sig- nificantly enhanced compared to the oral control group (22.3%). Moreover, the relative bioavailability of nimodipine was 1.30- to 1.49-fold greater than that of the control group. The pharmacokinetics of intravenous nimodipine was not affected by kaempferol in contrast to those of oral nimodipine. Kaempferol significantly enhanced the oral bioavailability of nimo- dipine, which might be mainly due to inhibition of the CYP3A4-mediated metabolism of nimodipine in the small intestine and /or in the liver and to inhibition of the P-gp efflux transporter in the small intestine by kaempferol. The increase in oral bioavailability of nimodipine in the presence of kaempferol should be taken into consideration of potential drug interactions between nimodipine and kaempferol. Key wordsNimodipine, Kaempferol, Pharmacokinetics, Bioavailability, P-gp, CYP3A4, Rats Nimodipine is a dihydropyridine calcium channel blocker that has been shown to selectively dilate cerebral arteries and increase cerebral blood flow in animals and humans (Kazda et al., 1982). Its major therapeutic indication is for the prevention and treatment of delayed ischemic neurological disorders that often occur in patients with subarachnoid hemorrhages (Epstein and Loutzenhister, 1990; Scholz, 1997). Nimodipine is rapidly absorbed after oral administration and is widely dis- tributed throughout the body. Orally administered nimodipine is subject to an extensive first-pass hepatic metabolism from the portal circulation, resulting in a low systemic bioavail- ability (Maruhn et al., 1985; Suwelack et al., 1985). Usually only the parent compound is active and most of the metabolic steps involve reactions catalyzed by cytochrome P450 (CYP) enzymes. CYP enzymes have been shown to catalyze pyridine