Pharmacokinetics of the anti-AIDS drug 2',3'-dideoxyinosine in the rat.

The pharmacokinetics of 2',3'-dideoxyinosine (ddlno) was examined in the male Fischer 344 rat using reversed phase HPLC with UV and radiochemical detection. Following iv doses of 12, 25, and 100 mg/kg, the parent drug was rapidly eliminated from plasma (mean residence time, 6.3 min; systemic clearance, 64 ml/min/kg). The mean terminal elimination half-life was 28 min and the volume of distribution at steady state was 0.39 liter/kg. Orally administered [3H]ddlno (100 mg/kg) was not significantly bioavailable in the rat, with only 8-11% of the dose absorbed as the parent compound over a 2 hr period. Peak plasma drug concentrations occurred 10 to 20 min following oral administration. Solution stability data suggested that ddlno was unstable at gastric pH (pH 1, t1/2 less than 30 sec). However, elevation of gastric pH with sodium bicarbonate prior to oral administration of ddlno was not effective in increasing the bioavailability of the parent drug. The drug and its metabolic products were extensively distributed into rat tissue 48 hr after iv or oral administration. Following iv infusion of [3H]ddlno to steady state conditions, the highest tissue-to-plasma ratios of radioactivity were found in the kidney (2.2), liver (1.7), and spleen (1.5). Renal clearance accounted for 99% of the eliminated dose. Liver perfusion studies showed that ddlno was not subject to significant hepatic clearance (less than 10%) and that the metabolism was not inducible with phenobarbital.