Isolation and identification of a metabolite of cidofovir from rat kidney

• Published in: Journal of pharmaceutical and biomedical analysis Vol. 16; no. 8; pp. 1349 - 1356
• Main Authors: Eisenberg, Eugene J, Lynch, Geoffrey R, Bidgood, Alison M, Krishnamurty, Krish, Cundy, Kenneth C
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.04.1998; Elsevier Science
• Subjects: Analysis; Animals; Antiviral Agents - administration & dosage; Antiviral Agents - isolation & purification; Antiviral Agents - metabolism; Biological and medical sciences; Chromatography, High Pressure Liquid - methods; Cidofovir; Cidofovir–phosphocholine; Cytosine - administration & dosage; Cytosine - analogs & derivatives; Cytosine - isolation & purification; Cytosine - metabolism; Dose-Response Relationship, Drug; Drug metabolism; General pharmacology; High-performance liquid chromatography; Injections, Intravenous; Kidney; Kidney - chemistry; Kidney - metabolism; Magnetic Resonance Spectroscopy; Male; Medical sciences; Nuclear magnetic resonance; Organophosphonates; Organophosphorus Compounds - administration & dosage; Organophosphorus Compounds - isolation & purification; Organophosphorus Compounds - metabolism; Pharmacology. Drug treatments; Rats; Drug metabolism; Cidofovir; Cidofovir–phosphocholine; Nuclear magnetic resonance; High-performance liquid chromatography; Kidney; Purification; Intravenous administration; Rat; Metabolite; Rodentia; HPLC chromatography; Identification; Metabolism; Vertebrata; Mammalia; Animal; Antiviral; Qualitative analysis; Extraction; Ion exchange resin; Mass spectrometry
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/S0731-7085(97)00162-3

Cidofovir is an acyclic nucleotide analog with potent and broad-spectrum antiviral activity against adenoviruses and herpesviruses including cytomegalovirus (CMV). Cidofovir undergoes intracellular phosphorylation by host enzymes to cidofovir phosphate and cidofovir diphosphate (the active form). An unidentified metabolite has been observed previously in rat tissues and in urine of rabbits, rats and monkeys dosed with cidofovir. In the present study, this metabolite was isolated from rat kidney following an intravenous dose of 100 mg kg −1 cidofovir. The metabolite (metabolite I) was separated from cidofovir and impurities using extraction on anion-exchange resin followed by preparative normal and reversed-phase high-performance liquid chromatography (HPLC). The isolated metabolite I was subjected to proton, 13C and phosphorus nuclear magnetic resonance (NMR) and matrix-assisted laser desorption/ionization mass spectroscopy, and confirmed to be cidofovir–phosphocholine. The uptake of cidofovir by rat kidney was saturated at an intravenous dose of 100 mg kg −1, probably as a result of saturation of the renal tubular secretion pathway. However, the relative abundance of cidofovir phosphocholine was not affected by dose.