EFFECT OF ORAL PROBENECID COADMINISTRATION ON THE CHRONIC TOXICITY AND PHARMACOKINETICS OF INTRAVENOUS CIDOFOVIR IN CYNOMOLGUS MONKEYS

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.