Effects of pravastatin on the pharmacokinetic parameters of nimodipine after oral and intravenous administration in rats: Possible role of CYP3A4 inhibition by pravastatin

Abstract

Objective:The aim of this study was to investigate the effects of pravastatin on the pharmacokinetics of nimodipine in rats.Materials and Methods:The effect of pravastatin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. Nimodipine was administered to rats intravenously (3 mg/kg) and orally (12 mg/kg) with pravastatin (0.3 and 1 mg/kg).Results:Pravastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC50) of 14 µM. Compared with the oral control group, the area under the plasma concentration-time curve (AUC0-∞) of nimodipine was increased significantly. Consequently, the absolute bioavailability (AB) of nimodipine with pravastatin (1 mg/kg) was 31.1%, which was significantly enhanced compared with the oral control group. Moreover, the relative bioavailability (RB) of nimodipine was 1.12- to 1.31-fold greater than that of the control group.Conclusions:The enhanced oral bioavailability of nimodipine might be mainly due to inhibition of the CYP3A-mediated metabolism of nimodipine in the small intestine and/or in the liver and due to reduction of the total body clearance rather than both to inhibition of the P-gp efflux transporter in the small intestine and reduction of renal elimination of nimodipine by pravastatin. The increase in the oral bioavailability of nimodipine with pravastatin should be taken into consideration of potential drug interactions between nimodipine and pravastatin.

Pharmacokinetic drug–drug interactions between 1,4-dihydropyridine calcium channel blockers and statins: factors determining interaction strength and relevant clinical risk management

“…The addition of pravastatin (1 mg/kg) increased the area under the plasma concentration–time curve from time zero to infinity (AUC 0–∞ ) and absolute bioavailability of oral nimodipine by 30.9% and 31.1%, respectively. However, the pharmacokinetics of IV nimodipine were not affected by the concomitant use of pravastatin, in contrast to those of oral nimodipine 10. The enhanced oral bioavailability of nimodipine might be mainly due to inhibition of the CYP3A-mediated metabolism of nimodipine in the small intestine and/or in the liver.…”

“…Pravastatin is known to be a statin that is not primarily metabolized by the CYP system, and it is not an object drug susceptible to CYP inhibitors or substrates. However, a CYP3A4 inhibition assay indicated that pravastatin could impair CYP3A4 enzyme activity in a concentration-dependent manner, with a 50% maximal inhibition concentration (IC 50 ) of 14 μM 10. The combination use of nimodipine and pravastatin is common in clinical practice.…”

“…Table 1 lists the DDI potential in combination use of DHP-CCBs and statins, along with a “not recommended” category and a “recommended, monitor therapy” category. 10 – 18…”

“…However, a CYP3A4 inhibition assay indicated that pravastatin could impair CYP3A4 enzyme activity in a concentration-dependent manner, with a 50% maximal inhibition concentration (IC 50 ) of 14 μM. 10 The combination use of nimodipine and pravastatin is common in clinical practice.…”

Isolated Hemopericardium after Initiation of Rivaroxaban: Implications and Potential Mechanisms

“…Given the above described pharmacokinetics of rivaroxaban, it is possible that the co-administration of Cyclobenzaprine and Pravastatin, both minor substrates of CYP 3A4. 10,11 and thus competitive compounds, lead to a higher serum concentration of metabolically active rivaroxaban and thus an increased bleeding risk.…”