Korean J Physiol Pharmacol.  2013 Jun;17(3):245-251. 10.4196/kjpp.2013.17.3.245.

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

• Lee CK
• Choi JS
• Bang JS

• KMID: 1429305
• DOI: http://doi.org/10.4196/kjpp.2013.17.3.245

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 microM 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-infinity 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.

Keyword

Bioavailability; CYP3A4; Fluvastatin; P-glycoprotein; Repaglinide

MeSH Terms

Administration, Intravenous
Animals
Area Under Curve
Biological Availability
Blood Glucose
Carbamates
Drug Interactions
Fatty Acids, Monounsaturated
Indoles
Intestine, Small
Liver
P-Glycoprotein
Piperidines
Plasma
Rats
Blood Glucose
Carbamates
Fatty Acids, Monounsaturated
Indoles
P-Glycoprotein
Piperidines

Figure

• 

  Fig. 1 Inhibitory effects of ketoconazole (A) and fluvastatin (B) on CYP3A4 activity. The result is expressed as the percent of inhibition.

• 

  Fig. 2 Rhodamine-123 retention. MCF-7/ADR cells were preincubated with fluvastatin for 30 min after incubation of MCF-7/ADR cells with 20 µM R-123 for 90 min. Data represent mean±SD of 6 separate samples (significant versus the control MCF-7 cells, *p<0.05, **p<0.01).

• 

  Fig. 3 Mean blood glucose-time profiles in rats after oral (0.5 mg/kg) administration of repaglinide in the presence or absence of fluvastatin (1 and 3 mg/kg; n=6, each). Bars represent the standard deviation; Oral administration of 0.5 mg/kg repaglinide (control; solid circles ●), with 1 mg/kg fluvastatin (open circles ○) and with 3 mg/kg fluvastatin (solid triangles ▼) *p<0.05 significant difference compared to control.

• 

  Fig. 4 Mean blood glucose-time profiles in rats after intravenous (0.2 mg/kg) administration of repaglinide in the presence or absence of fluvastatin (1 and 3 mg/kg; n=6, each). Bars represent the standard deviation; Intravenous administration of 0.2 mg/kg repaglinide (control; solid circles ●), with 1 mg/kg fluvastatin (open circles ○) and with 3 mg/kg fluvastatin (solid triangles ▼).

• 

  Fig. 5 Mean plasma concentration-time profiles of repaglinide after oral (0.5 mg/kg) administration of repaglinide to rats in the presence or absence of fluvastatin (1 and 3 mg/kg; n=6, each). Bars represent the standard deviation; Oral administration of 0.5 mg/kg repaglinide (control; solid circles ●), with 1 mg/kg fluvastatin (open circles ○) and with 3 mg/kg fluvastatin (solid triangles ▼) *p<0.05 significant difference compared to control.

• 

  Fig. 6 Mean plasma concentration-time profiles of repaglinide after intravenous (0.2 mg/kg) administration of repaglinide to rats in the presence or absence of fluvastatin (1 and 3 mg/kg; n=6, each). Bars represent the standard deviation; Intravenous administration of 0.2 mg/kg repaglinide (control; solid circles ●), with 1 mg/kg fluvastatin (open circles ○) and with 3 mg/kg fluvastatin (solid triangles ▼).

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