Effects of Aspirin on the Bioavailability and Pharmacokinetics of Repaglinide: Possible Role of Cytochrome P450 3A Isoforms Inhibition by Aspirin

The purpose of this study was to investigate the effects of aspirin on the bioavailability and pharmacokinetics of repaglinide in rats. Repaglinide and aspirin interact with cytochrome P450 (CYP) 3A isoforms. Clinically, repaglinide and aspirin can be prescribed for the prevention or treatment of diabetes and cardiovascular disease as complications of diabetes. The effect of aspirin on P-glycoprotein (P-gp) and CYP3A4 activity was evaluated. The pharmacokinetic parameters of repaglinide and blood glucose concentrations were also determined in rats after oral (0.5 mg/kg) and intravenous (0.2 mg/kg) administration of repaglinide in the presence and absence of aspirin (5 and 20 mg/kg). Aspirin could inhibit CYP3A4 activity with an IC50 value of 15.0 μM, but aspirin did not inhibit P-gp activity by comparing with the relative cellular uptake of rhodamine-123. Compared to the oral control group, aspirin significantly increased the AUC0–∞ and the Cmax of repaglinide by 36.6% and 18.8%, respectively, while the CL/F ratio was significantly decreased by aspirin. Aspirin also increased the absolute bioavailability (A.B.) of repaglinide by 36.9% compared to the oral control group. Moreover, the relative bioavailability (R.B.) of repaglinide was 1.13 to 1.37 times greater than that in the control group. Oral aspirin (20 mg/kg) could significantly decrease the blood glucose concentrations after oral (0.5 mg/kg) administration of repaglinide compared to the oral control groups. Aspirin enhanced the oral bioavailability of repaglinide, which may be attributed to the inhibition of CYP3A isoform mediated metabolism in the small intestine and/or in the liver rather than to the inhibition of P-gp in the small intestine and/or the reduction of renal elimination of repaglinide by aspirin. The increase in the oral bioavailability of repaglinide should be taken into consideration as potential drug interaction when coadministering repaglinide and aspirin. Furthermore, the blood glucose concentration should be carefully monitored during their coadministration.