DRUG INTERACTION BETWEEN PIOGLITAZONE OR METFORMIN AND DILTIAZEM IN RATS

Abstract

Diltiazem, a substrate of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), is a calcium channel blocker that is widely used for the treatment of angina, supraventricular arrhythmias and hypertension. The present study aimed to investigate the effect of pioglitazone or metformin on the pharmacokinetics of diltiazem in rats. Pharmacokinetic parameters of diltiazem were determined in rats after oral administration of diltiazem (15 mg/kg) in the presence and absence of pioglitazone (1 or 3 mg/kg) or metformin (10 or 30 mg/kg). The presence of pioglitazone significantly (1 mg/kg, P < 0.05; 3 mg/kg, P <0.01) increased the area under the plasma concentration-time curve (AUC) of diltiazem. Pioglitazone significantly (P < 0.05) increased the peak concentration (C_(max)) of diltiazem. Pioglitazone increased the terminal half-life (t_(1/2)) of diltiazem but not significantly. Consequently, the relative bioavailability (RB) of diltiazem was increased by 1.49?C to 1.68?Cfold than those of the control group. Pioglitazone increased the terminal half-life (t_(1/2)) of diltiazem but not significantly. It did not change the peak concentration time (T_(max)) of diltiazem. The enhanced bioavailability of diltiazem might be due to the decreased first-pass metabolism (CYP3A) of diltiazem in the intestine and/or liver competitively. The presence of 3 mg/kg of pioglitazone significantly (P <0.05) increased the area under the plasma concentration?Ctime curve (AUC) of desacetyldiltiazem. Pioglitazone increased the peak plasma concentration (C_(max)) and the terminal half-life (t_(1/2)) of desacetyldiltiazem but not significantly. Consequently, the relative bioavailability (RB) of desacetyldiltiazem increased by 1.32-to 1.48-Cfold than those of the control group. The presence of metformin, antioxidant, significantly altered the pharmacokinietic parameters of diltiazem. Compared to the oral control group (given diltiazem alone), the presence (10 and 30 mg/kg) of metformin significantly (P < 0.05) increased the area under the plasma concentration-time curve (AUC_(0-∞)) and peak plasma concentration (C_(max)) of diltiazem. Consequently, the relative bioavailability (RB) of diltiazem was increased approximately 1.34-to 1.54-fold in the presence of metformin. Metformin increased the terminal half-life (t_(1/2)) of diltiazem but not significantly. It did not change in the peak concentration time (T_(max)) of diltiazem. The presence of 30 mg/kg of metformin significantly (P <0.05) increased the area under the plasma concentration?Ctime curve (AUC) of desacetyldiltiazem. Metformin increased the peak plasma concentration (C_(max)) and the terminal half-life (t_(1/2)) of desacetyldiltiazem but not significantly. Consequently, the relative bioavailability (RB) of desacetyldiltiazem increased by 1.26?C to 1.41?Cfold than those of the control group. Metformin increased the terminal half-life (t_(1/2)) of desacetyldiltiazem but not significantly. It did not change the peak concentration time (T_(max)) of desacetyldiltiazem. The presence of pioglitazone or metformin significantly enhanced the oral bioavailability of diltiazem. Based on the results, the diltiazem dosage adjustment should be taken into consideration for safe and effective therapy of hypertension disease with diabetic complication when diltiazem is used concomitantly with pioglitzone or metformin in the clinical setting.