PHARMACOKINETICS, BIOAVAILABILITY, METABOLISM, AND TISSUE DISTRIBUTION OF CIDOFOVIR (HPMPC) AND CYCLIC HPMPC IN RATS

The pharmacokinetics, distribution, and metabolism of [C-14]cidofovir and its cyclic analog -oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosin e; [C-14]cyclic HPMPC} were compared after administration to Sprague-D awley rats. After intravenous (iv) administration of [C-14]cidofovir ( 3 or 5 mg/kg) or [C-14]cyclic HPMPC (5 mg/kg), plasma concentrations o f total radioactivity declined in a multiexponential manner for both d rugs with terminal half-lives of 7-11 hr. No metabolites of cidofovir were observed in plasma. However, iv [C-14]cyclic HPMPC was converted in vivo to cidofovir (3.9% of the AUC of total radioactivity). The cor rected half-life of cyclic HPMPC was 0.53 +/- 0.05 hr. The clearance o f iv cidofovir (0.60-0.79 liter/hr/kg) was significantly less than tha t of cyclic HPMPC (1.10 +/- 0.12 liter/hr/kg). Cyclic HPMPC was more e fficiently secreted by the kidney than cidofovir. The steady-state vol ume of distribution of cyclic HPMPC (0.32 +/- 0.5 liter/kg) was substa ntially 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 similar to 20-fold higher for cidofovir (6.6 mu g-eq/g) than for cyclic HPMPC, w hereas levels of radioactivity in the remaining tissues were similar f or both drugs. This is consistent with the improved therapeutic index observed for cyclic HPMPC in animals. After iv administration of [C-14 ]cidofovir (3 mg/kg), concentrations in most tissues declined with hal f-lives >12 hr, presumably reflecting the long intracellular half-life of phosphorylated drug. Kidneys and liver of animals given iv [C-14]c idofovir (5 mg/kg) contained unchanged cidofovir (35-65%), metabolite I (attributed to cidovofir phosphocholine) (29-60%), and a peak coelut ing with cyclic HPMPC on three different HPLC systems (metabolite II) (5-7%). Kidneys, liver, and lung of animals given iv [C-14]cyclic HPMP C 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% an d 3.50 +/- 1.07%, respectively, based on total radioactivity.