Isolation and identification of a metabolite of cidofovir from rat kidney.
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.
Eisenberg
E J
EJ
Gilead Sciences, Foster City, CA 94044, USA.
Lynch
G R
GR
Bidgood
A M
AM
Krishnamurty
K
K
Cundy
K C
KC
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000302:isolation & purification* / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D000077404:Cidofovir; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D007668:Kidney / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000302:isolation & purification* / Q000378:metabolism*; D051381:Rats
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D000077404:Cidofovir