| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 1998 Oxford University Press
other |
Effect of Oral Probenecid Coadministration on the Chronic Toxicity and Pharmacokinetics of Intravenous Cidofovir in Cynomolgus Monkeys
*Gilead Sciences, Inc. 333 Lakeside Drive, Foster City, California 94404
ClinTrials BioResearch Laboratories Ltd. 87 Senneville Road, Senneville, Quebec, Canada H9X 3R3
Received October 17, 1997; accepted May 1, 1998
In animals and humans, intravenous administration of the antiviral nucleotide analogue cidofovir results in a dose-limiting nephrotoxicity characterized by damage to the proximal tubular epithelial cells. Probenecid, a competitive inhibitor of organic anion transport in the proximal tubular epithelial cells, was evaluated for its effect on the chronic toxicity and pharmacokinetics of cidofovir. Cynomolgus monkeys (5/sex/group) received cidofovir for 52 consecutive weeks as a once weekly intravenous bolus injection at 0 (saline), 0.1, 0.5, or 2.5 mg/kg/dose 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). Cidofovir-associated histopathological changes were seen only in the kidneys, testes, and epididymides. Nephrotoxicity (mild to moderate cortical tubular epithelial cell karyomegaly, tubular dilatation, basement membrane thickening) was present only in monkeys receiving 2.5 mg/kg/dose cidofovir without probenecid. The incidence and severity of testicular (hypo- and aspermatogenesis) and epididymal (severe oligo- and aspenmia) changes were increased in monkeys administered cidofovir at 2.5 mg/kg/dose, either alone or in combination with oral probenecid. Renal drug 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 (as measured by AUC) that was significantly greater in monkeys administered cidofovir alone (312% increase in males, 98% in females) than in those coadministered probenecid (32% increase in males, 3% in females). These results demonstrate that oral probenecid coadministration protects against the morphological evidence of nephrotoxicity and the accompanying decrease in renal clearance in monkeys receiving chronic intravenous cidofovir treatment.
Key Words: l-[(S)-3-hydroxy-2-phosphonomethoxy)propyl]cyto-sine; Cidofovir; Cidofovir injection (Vistide); biological activity; nucleotide analogue with antiherpesvirus activity.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. C. Quenelle, M. N. Prichard, K. A. Keith, D. E. Hruby, R. Jordan, G. R. Painter, A. Robertson, and E. R. Kern Synergistic Efficacy of the Combination of ST-246 with CMX001 against Orthopoxviruses Antimicrob. Agents Chemother., November 1, 2007; 51(11): 4118 - 4124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Eraly, K. T. Bush, R. V. Sampogna, V. Bhatnagar, and S. K. Nigam The Molecular Pharmacology of Organic Anion Transporters: from DNA to FDA? Mol. Pharmacol., March 1, 2004; 65(3): 479 - 487. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. De Clercq Clinical Potential of the Acyclic Nucleoside Phosphonates Cidofovir, Adefovir, and Tenofovir in Treatment of DNA Virus and Retrovirus Infections Clin. Microbiol. Rev., October 1, 2003; 16(4): 569 - 596. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Roy, R. Baker, K. Washburn, and M. Bray Aerosolized Cidofovir Is Retained in the Respiratory Tract and Protects Mice against Intranasal Cowpox Virus Challenge Antimicrob. Agents Chemother., September 1, 2003; 47(9): 2933 - 2937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Wolf, C. A. Rodriguez, M. Mucci, A. Ingrosso, B. A. Duncan, and D. J. Nickens Pharmacokinetics and Renal Effects of Cidofovir with a Reduced Dose of Probenecid in HIV-Infected Patients with Cytomegalovirus Retinitis J. Clin. Pharmacol., January 1, 2003; 43(1): 43 - 51. [Abstract] [Full Text]
|
|
|
|
|
|
K. C. Cundy, P. Barditch-Crovo, B. G. Petty, A. Ruby, M. Redpath, H. S. Jaffe, and P. S. Lietman Clinical Pharmacokinetics of 1-[((S)-2-Hydroxy-2-Oxo-1,4,2-Dioxaphosphorinan-5-yl)methyl]cytosine in Human Immunodeficiency Virus-Infected Patients Antimicrob. Agents Chemother., February 1, 1999; 43(2): 271 - 277. [Abstract] [Full Text]
|
|