title: Pharmacokinetics of cidofovir in monkeys. Evidence for a prolonged elimination phase representing phosphorylated drug.
abstract: After intravenous administration of [14C]cidofovir to African green monkeys (43 mg/kg, 29.5 microCi/kg), the drug distributed rapidly into extracellular fluid. Concentrations of radioactivity in plasma were described by a three-compartment model with alpha, beta, and gamma half-lives of 0.67, 3.02, and 36.0 hr, respectively (N = 3). These phases are believed to represent renal elimination, efflux of free cidofovir from cells, and efflux from cells of cidofovir produced from dephosphorylation of metabolites, respectively. Less than 5% of the dose was phosphorylated, based on the proportion of total AUC in the gamma-phase. The clearance of cidofovir (211 +/- 16.6 ml/hr/kg) was dependent on dose and exceeded the theoretical glomerular filtration rate. Concentrations of cidofovir in kidney declined with a half-life of 23 hr and were > 1,000-fold higher than plasma levels by 120 hr. Clearance of cidofovir after multiple intravenous doses of 4.9 mg/kg/day (18.5 microCi/kg/day) decreased significantly by day 10, consistent with the observed nephrotoxicity. Oral and subcutaneous bioavailabilities of cidofovir were 21.8 +/- 9.44 and 98.5 +/- 15.8%, respectively. After intravenous administration of [14C]cidofovir to cynomolgus monkeys (10 mg/kg, 100 microCi/kg) alone or 1 hr after oral probenecid (30 mg/kg), mean +/- SD (N = 3) urinary recoveries of total radioactive dose were 91.4 +/- 11.3% and 94.4 +/- 29.8%, respectively, at 7 days postdose. The mean +/- SD half-lives of the terminal elimination phases were 33.3 +/- 10.6 and 24.4 +/- 5.0 hr, respectively. Cidofovir accounted for 98% of the radioactivity recovered in urine; the remainder was attributed to cidofovir phosphocholine. The prolonged elimination phase observed in monkeys is consistent with the long intracellular half-life of phosphorylated cidofovir in vitro and supports infrequent dosing of the drug for antiviral therapy.
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: M J
authors.initials: MJ
authors.lastname: Hitchcock
authors.forename: W A
authors.initials: WA
authors.lastname: Lee
mesh_terms: D000279:Administration, Cutaneous; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D001682:Biological Availability; D002250:Carbon Radioisotopes; D002522:Chlorocebus aethiops; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D010766:Phosphorylation; D011339:Probenecid / Q000494:pharmacology; D014777:Virus Diseases / Q000188:drug therapy
chemical_list: D000998:Antiviral Agents; D002250:Carbon Radioisotopes; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D000077404:Cidofovir; D011339:Probenecid