Kc. Cundy et al., PHARMACOKINETICS, BIOAVAILABILITY, METABOLISM, AND TISSUE DISTRIBUTION OF CIDOFOVIR (HPMPC) AND CYCLIC HPMPC IN RATS, Drug metabolism and disposition, 24(7), 1996, pp. 745-752
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.