Pharmacokinetics and metabolism of the novel synthetic C-nucleoside, 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-iodobenzene: a potential mimic of 5-iodo-2'-deoxyuridine.
1-(2-Deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-iodobenzene (5-IDFPdR) is one of the several unnatural 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-substituted-benzenes recently synthesized for evaluation as anticancer, antiviral and diagnostic imaging agents. This class of C-nucleosides was designed to exploit several potential advantages relative to classical 5-substituted-2'-deoxyuridines, including stability towards phosphorolysis by pyrimidine phosphorylase, increased lipophilicity that may alter their ability to cross the blood-brain-barrier, and a greater resistance towards catabolism and deiodination. The physiochemical evaluation of 5-IDFPdR showed high lipophilicity (log P = 2.8), moderately high protein binding (70-75%), stability towards phosphorolysis (e.g. no evidence of metabolic deglycosylation) by thymidine phosphorylase, and minimal microsomal metabolism in vitro. Pharmacokinetic studies of 5-IDFPdR in rat were characterized by a short elimination half-life (9-12 min), modest urinary elimination in pooled 0-24 h urine specimens (10-14%, including 2% as unconjugated drug) and high oral bioavailability (F = 0.96). Both glucuronide and sulfate metabolites were present in urine. Glucuronidation was the predominant conjugation pathway.
Khalili
Panteha
P
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Naimi
Ebrahim
E
Knaus
Edward E
EE
Wiebe
Leonard I
LI
D000818:Animals; D002417:Cattle; D003853:Deoxyribonucleosides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D007065:Idoxuridine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D018716:Molecular Mimicry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012266:Ribose / Q000031:analogs & derivatives; D012710:Serum Albumin, Bovine / Q000378:metabolism
C483745:1-(2-deoxyribofuranosyl)-2,4-difluoro-5-iodobenzene; D003853:Deoxyribonucleosides; D012710:Serum Albumin, Bovine; D012266:Ribose; D007065:Idoxuridine