Effects of Fluvastatin on the Pharmacokinetics of Repaglinide: Possible Role of CYP3A4 and P-glycoprotein Inhibition by Fluvastatin

Abstract

The purpose of this study was to investigate the effects of fluvastatin on the pharmacokinetics of repaglinide in rats. The effect of fluvastatin on P-glycoprotein and CYP3A4 activity was evaluated. The pharmacokinetic parameters and blood glucose concentrations were also determined after oral and intravenous administration of repaglinide to rats in the presence and absence of fluvastatin. Fluvastatin inhibited CYP3A4 activity in a concentration-dependent manner with a 50% inhibition concentration(IC50) of 4.1 µM and P-gp activity. Compared to the oral control group, fluvastatin significantly increased the AUC and the peak plasma level of repaglinide by 45.9% and 22.7%, respectively. Fluvastatin significantly decreased the total body clearance (TBC) of repaglinide compared to the control. Fluvastatin also significantly increased the absolute bioavailability (BA) of repaglinide by 46.1% compared to the control group. Moreover, the relative BA of repaglinide was 1.14- to 1.46-fold greater than that of the control. Compared to the i.v. control, fluvastatin significantly increased the AUC0-∞ of i.v. administered repaglinide. The blood glucose concentrations showed significant differences compared to the oral controls. Fluvastatin enhanced the oral BA of repaglinide, which may be mainly attributable to the inhibition of the CYP3A4-mediated metabolism of repaglinide in the small intestine and/or liver, to the inhibition of the P-gp efflux transporter in the small intestine and/or to the reduction of TBC of repaglinide by fluvastatin. The study has raised the awareness of potential interactions during concomitant use of repaglinide with fluvastatin. Therefore, the concurrent use of repaglinide and fluvastatin may require close monitoring for potential drug interactions.

Enhanced oral bioavailability of fluvastatin by using nanosuspensions containing cyclodextrin

“…3 The recommended dose is 20 or 40 mg daily, 1 hour is required to reach peak plasma concentration, and the volume of distribution of FVT is 330 L. The oral bioavailability of FVT is as low as 30% due to the slow dissolution rate in the intestinal tract and obvious first-pass effect. 4 In addition, considering the long-term use of FVT, it is an essential requirement to enhance FVT bioavailability and sustain its release to lower both the dose and the frequency, hence improving patient tolerability. Clinically, the increase in low-density lipoproteins (LDLs) in plasma concentration leads to vascular stenosis, which carries the risk of atherosclerosis, coronary artery disease, and plague and has life-threatening consequences.…”

Improvement of fluvastatin bioavailability by loading on nanostructured lipid carriers

“…3 FLV has some disadvantages, including poor bioavailability (∼30%) as a result of low solubility, and short half-life (t 1/2 ) of 1-3 hours, and therefore, short duration of action. 4 Also, by taking into consideration the long-term use of FLV, it is an essential requirement to enhance FLV bioavailability and sustain its release that will lower both the dose and the frequency, hence improve patient tolerability.…”

Evaluation of pharmacokinetic and pharmacodynamic interaction between repaglinide and atazanavir in healthy, diabetic and hepatic impaired rats: possible inhibition of CYP3A, OATP, and P-glycoprotein transporters

“…The repaglinide pharmacokinetics was further complicated because of active hepatic uptake of repaglinide by OATP uptake transporter and it is a substrate for the OATP transporter [24]. Repaglinide also act as a substrate for P-glycoprotein which can significantly contribute to potential drug-drug interactions with other P-gp substrate or inhibitors [25]. HIV protease inhibitors have identified as a substrates, inhibitors or inducers of CYP3A4, OATP and P-gp.…”