Biochemical and pharmacokinetic evaluation of a novel pyrimidine nucleoside nitric oxide donor as a potential anticancer/antiviral agent.
The objective of this study was to determine the physiochemical, biochemical and pharmacokinetic properties of 5-iodo-3'-O-nitro-2'-deoxyuridine (INUdR), a novel prodrug releasing both nitric oxide (NO) and 5-iodo-2'-deoxyuridine. The INUdR partition coefficient (log P=1.12) was determined by both the shake-flask method and by calculation using Interactive Analysis Log P Program. In vitro binding of INUdR to bovine serum albumin (BSA) was estimated using an ultrafiltration method to be 65 to 77%, depending on the INUdR concentration. INUdR was stable in phosphate buffer (pH 7.4) and in water, at both ambient temperature and at 37 degrees C. INUdR was resistant to phosphorolysis when incubated with thymidine phosphorylase. Plasma, L-cysteine and glutathione catalyzed release of NO from INUdR, as determined using the Griess reaction. In all three systems, the release of NO by INUdR was equal to or greater than that of the reference drug isosorbide dinitrate. The pharmacokinetics of INUdR following single intravenous bolus and oral doses of INUdR (40 mg/kg) to male Sprague-Dawley rats were characterized by a short elimination half-life (T(1/2) 0.27 h), a large steady-state volume of distribution (V(ss) 0.89 l/kg) and high oral bioavailability (F=0.95). In conclusion, INUdR lipophilicity, shelf-stability, and resistance towards catabolic breakdown by thymidine phosphorylase, together with its non-spontaneous, yet considerable NO release, constitute favorable characteristics of a potential anticancer/antiviral agent.
Khalili
Panteha
P
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, 3118 Dent.-Pharm. Bldg, Edmonton, Alberta T6G 2N8, Canada.
Naimi
Ebrahim
E
Sun
Wei Yan
WY
Knaus
Edward E
EE
Wiebe
Leonard I
LI
D000818:Animals; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D007065:Idoxuridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D020030:Nitric Oxide Donors / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000378:metabolism
C484081:5-iodo-3'-O-nitro-2'-deoxyuridine; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D020030:Nitric Oxide Donors; D012710:Serum Albumin, Bovine; D007065:Idoxuridine