ISOLATION AND IDENTIFICATION OF A METABOLITE OF CIDOFOVIR FROM RAT-KIDNEY

Cidofovir is an acyclic nucleotide analog with potent and broad-spectr um antiviral activity against adenoviruses and herpesviruses including cytomegalovirus (CMV). Cidofovir undergoes intracellular phosphorylat ion by host enzymes to cidofovir phosphate and cidofovir diphosphate ( the active form). An unidentified metabolite has been observed previou sly in rat tissues and in urine of rabbits, rats and monkeys dosed wit h cidofovir. In the present study this metabolite was isolated from ra t 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 norm al and reversed-phase high-performance liquid chromatography (HPLC). T he isolated metabolite I was subjected to proton, C-13 and phosphorus nuclear magnetic resonance (NMR and matrix-assisted laser desorption/i onization mass spectroscopy, and confirmed to be cidofovir-phosphochol ine. The uptake of cidofovir by rat kidney was saturated at an intrave nous dose of 100 mg kg(-1), probably as a result of saturation of the renal tubular secretion pathway. However, the relative abundance of ci dofovir phosphocholine was not affected by dose. (C) 1998 Elsevier Sci ence B.V. All rights reserved.