Pharmacokinetics of nitroglycerin after parenteral and oral dosing in the rat

The pharmacokinetics of nitroglycerin was characterized in detail using venous plasma after different intravenous bolus doses (0.15–2.48 mg/kg), intra‐arterial infusion (8.2 μg/min over 5 h), and oral doses (7–100 mg/kg). Venous plasma clearance was found to be ∼650 mL/kg and was independent of the intravenous or intra‐arterial dose. This confirmed earlier reports that the venous plasma clearance of nitroglycerin in rats exceeded the value of normal cardiac output. A terminal half‐life of ∼15 min was observed after high intravenous bolus doses of nitroglycerin. This slow disappearance phase was likely rate limited by redistribution of drug back into the plasma. The bioavailability of oral nitroglycerin (F) showed an apparent Michaelis‐Menten dependency on dose. F was <5% at doses <20 mg/kg, but increased to a plateau of ∼20% from 50–100 mg/kg. First‐pass metabolism of nitroglycerin is thus apparently controlled by at least two systems (sites or enzymes). Coadministration of mannitol hexanitrate, a potential competitive inhibitor of first‐pass metabolism, did not increase F.