title: Effect of probenecid on the distribution, metabolism, and excretion of cidofovir in rabbits.
abstract: The effect of concomitant probenecid on the tissue distribution, metabolism, and urinary excretion of cidofovir was examined in New Zealand white rabbits. Two groups of six male rabbits received intravenous [3H]cidofovir (5 mg/kg, 20 mu Ci/kg) alone or with concomitant intravenous probenecid (90 mg/kg). Radioactivity in kidney at 15 min postdose was decreased 70% by probenecid; plasma levels at 15 min postdose were increased 65% by probenecid. These effects were diminished at later time points. The estimated elimination half-life of cidofovir from the kidney was 16 hr in the presence of probenecid and 11 hr without probenecid. Two additional groups of six rabbits received intravenous [14C]cidofovir (15 mg/kg, 100 mu Ci/kg) alone or 1 hr after oral administration of probenecid (90 mg/kg). Radioactivity was highest in the kidney (approximately 700 mu g-eq/g at 30 min postdose). Probenecid did not affect the gross distribution of radioactivity. However, autoradiography of left kidneys revealed localization of the drug in the renal cortex; radioactivity in the cortex at 30 min postdose was decreased 50% by probenecid. These data are consistent with inhibition of tubular secretion of cidofovir by probenecid. More than 73% of the cidofovir dose was recovered in the urine in 24 hr. Urine contained unchanged cidofovir (>97%) and a metabolite coeluting with authentic cidofovir phosphocholine (2%). This metabolite also accounted for approximately 1-4% of the radioactivity in rabbit kidney.
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Cundy
authors.forename: Z H
authors.initials: ZH
authors.lastname: Li
authors.forename: W A
authors.initials: WA
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001345:Autoradiography; D000077404:Cidofovir; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D007275:Injections, Intravenous; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011339:Probenecid / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D011859:Radiography; D014018:Tissue Distribution; D014528:Uricosuric Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D014528:Uricosuric Agents; D003596:Cytosine; D000077404:Cidofovir; D011339:Probenecid