Sa. Lacy et al., EFFECT OF ORAL PROBENECID COADMINISTRATION ON THE CHRONIC TOXICITY AND PHARMACOKINETICS OF INTRAVENOUS CIDOFOVIR IN CYNOMOLGUS MONKEYS, TOXICOLOGICAL SCIENCES, 44(2), 1998, pp. 97-106
In animals and humans, intravenous administration of the antiviral nuc
leotide analogue cidofovir results in a dose-limiting nephrotoxicity c
haracterized by damage to the proximal tubular epithelial cells. Probe
necid, a competitive inhibitor of organic anion transport in the proxi
mal tubular epithelial cells, was evaluated for its effect on the chro
nic toxicity and pharmacokinetics of cidofovir. Cynomolgus monkeys (5/
sex/group) received cidofovir for 52 consecutive weeks as a once weekl
y intravenous bolus injection at 0 (saline), 0.1, 0.5, or 2.5 mg/kg/do
se alone or at 2.5 mg/kg/dose in combination with probenecid (30 mg/kg
/dose via oral gavage 1 h prior to cidofovir administration). Cidofovi
r-associated histopathological changes were seen only in the kidneys,
testes, and epididymides. Nephrotoxicity (mild to moderate cortical tu
bular epithelial cell karyomegaly, tubular dilatation, basement membra
ne thickening) was present only in monkeys receiving 2.5 mg/kg/dose ci
dofovir without probenecid. The incidence and severity of testicular (
hypo- and aspermatogenesis) and epididymal (severe oligo- and aspermia
) changes were increased in monkeys administered cidofovir at 2.5 mg/k
g/dose, either alone or in combination with oral probenecid, Renal dru
g clearance was decreased between Weeks 1 and 52 in the 2.5 mg/kg/dose
groups and resulted in an increased systemic exposure to cidofovir la
s measured by AUG) that was significantly greater in monkeys administe
red cidofovir alone (312% increase in males, 98% in females) than in t
hose coadministered probenecid (32% increase in males, 3% in females).
These results demonstrate that oral probenecid coadministration prote
cts against the morphological evidence of nephrotoxicity and the accom
panying decrease in renal clearance in monkeys receiving chronic intra
venous cidofovir treatment. (C) 1998 Society of Toxicology.