Abstract

The pharmacokinetics, distribution, and metabolism of [14C]cidofovir and its cyclic analog {[2-14C]-1-[((S)-2-hydroxy-2-oxo-1,4, 2-dioxaphosphorinan-5-yl)methyl]cytosine; [14C]cyclic HPMPC} were compared after administration to Sprague-Dawley rats. After intravenous (iv) administration of [14C]cidofovir (3 or 5 mg/kg) or [14C]cyclic HPMPC (5 mg/kg), plasma concentrations of total radioactivity declined in a multiexponential manner for both drugs with terminal half-lives of 7-11 hr. No metabolites of cidofovir were observed in plasma. However, iv [14C]cyclic HPMPC was converted in vivo to cidofovir (3.9% of the AUC of total radioactivity). The corrected half-life of cyclic HPMPC was 0.53 +/- 0.05 hr. The clearance of iv cidofovir (0.60-0.79 liter/hr/kg) was significantly less than that of cyclic HPMPC (1.10 +/- 0.12 liter/hr/kg). Cyclic HPMPC was more efficiently secreted by the kidney than cidofovir. The steady-state volume of distribution of cyclic HPMPC (0.32 +/- 0.5 liter/kg) was substantially less than that of cidofovir (0.9-3.0 liter/ kg). Concentrations in kidney at 24 hr after iv administration of 5 mg/kg were approximately 20-fold higher for cidofovir (6.6 micrograms-eq/g) than for cyclic HPMPC, whereas levels of radioactivity in the remaining tissues were similar for both drugs. This is consistent with the improved therapeutic index observed for cyclic HPMPC in animals. After iv administration of [14C]cidofovir (3 mg/kg), concentrations in most tissues declined with half-lives > 12 hr, presumably reflecting the long intracellular half-life of phosphorylated drug. Kidneys and liver of animals given iv [14C]cidofovir (5 mg/kg) contained unchanged cidofovir (35-65%), metabolite I (attributed to cidovofir phosphocholine) (29-60%), and a peak coeluting with cyclic HPMPC on three different HPLC systems (metabolite II) (5-7%). Kidneys, liver, and lung of animals given iv [14C]cyclic HPMPC contained cyclic HPMPC (1-6%), cidofovir (44-50%), and metabolite I (44-54%). The subcutaneous bioavailability of cidofovir was 91.5%. The subcutaneous and oral bioavailabilities of cyclic HPMPC were 82.7% and 3.50 +/- 1.07%, respectively, based on total radioactivity.