Comparative diltiazem plasma clearance in normotensive and hypertensive rats

Diltiazem plasma clearance was studied in normotensive (NR) and spontaneous hypertensive rats (SHR), either following intravenous bolus administration of 3 mg/kg (CLiv), or after 25 min of intravenous infusion (CL25) at different dose levels (1, 2, 4, and 8 mg/kg/30 min in NR; 0.5, 1, 2, and 4 mg/kg/30 min in SHR). The diltiazem pharmacokinetic profile fit a two-compartment open model better, both in NR and SHR. The CLiv of diltiazem was significantly higher in NR than in SHR. Following infusion, diltiazem plasma clearance increased for high levels of infused dose in NR and in SHR. For each level of dose, CI25 was significantly higher in NR than in SHR. For both groups of animals, CI25 values were significantly higher than their respective CIiv values. These results show the influence of hypertension on the pharmacokinetic characteristics of diltiazem, as well as the effect of its own vasodilator action. An increase in diltiazem clearance values may be due to an increase in hepatic blood flow that is a result of its vasodilator action.