Dose-ranging study of N^G-nitro-L-arginine pharmacokinetics in rats after bolus intravenous administration

Abstract

1. N^G-nitro-L-arginine (10, 30 and 100 mg/kg) was administered intravenously to the male Wistar rat. Plasma was collected over 48, 72 and 120h and was analysed for the drug by hplc. Pharmacokinetic parameters were calculated using a non-compartmental method.

2. Drug concentration-time profiles of individual rats after all doses studied exhibited secondary peaks, while geometric mean concentration-time curves showed plateaus.

3. N^G-nitro-L-arginine plasma concentrations divided by dose almost coincided. Pharmacokinetic parameters were not dose-dependent in the range of 10–30 mg/kg, but changed after 100mg/kg of N^G-nitro-L-arginine indicating some decline from linearity.

4. N^G-nitro-L-arginine is a low-extracted drug in rat as the total clearance was low (0.05–0.071/h/kg). Half-life and mean residence time were found to be long (17–30 and 23–40h, respectively). Despite its low lipophilicity, N^G-nitro-L-arginine exhibited large steady-state and terminal volumes of distribution (1.4–2.21/kg and 1.4–2.41/kg, respectively). Together with the double peak phenomenon, these results may be explained by assuming N^G-nitro-L-arginine is involved in a recirculation process in the body.