Metabolism and disposition of 2',3'-di-O-nitro-adenosine-5'-(N-ethyl-carboxamide) in dogs.
2',3'-Di-O-nitro-[8-3H]-adenosine-5'-(N-ethyl-carboxamide) (20 micrograms/kg) was denitrated completely within 1-3 hr in perorally and intravenously dosed dogs. Extremely rapid disappearance of the unchanged drug in serum was parallelled by the instantaneous appearance of mononitrates with 3'-mononitrate levels exceeding those of 2'-mononitrate three-fold. The mononitrates were eliminated with a half-life of 30-70 min, giving rise to the completely denitrated product, adenosine-5'-(N-ethyl-carboxamide) (NECA). The latter product was not further metabolized and was eliminated with a half-life of about 4 hr. Urinary excretion averaged 50% of the administered dose within 4 days and was represented essentially by the completely denitrated drug. Volatile 3H-label of the drug was found in serum and urine during in vivo experiments. Oral bioavailability of the drug was about 90%. In vitro studies indicated that thiols are involved in denitration and reactions are catalysed by glutathione S-transferases, which were partially purified from dog liver. Nitrate ester cleavage was more easily accomplished at the 2'-position than at the 3'-position of the drug and resulted in the liberation of inorganic nitrite. Comparison of in vitro denitration rates gave the following ranking order; 2',3'-di-O-nitro-NECA greater than isosorbide-2,5-dinitrate greater than 2'-nitro-NECA greater than 3'-nitro-NECA greater than isosorbide-2-mononitrate, while nitrate ester cleavage of isosorbide-5-mononitrate was not detectable.
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000031:analogs & derivatives*; D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation; D002855:Chromatography, Thin Layer; D004285:Dogs; D005260:Female; D005982:Glutathione Transferase / Q000302:isolation & purification / Q000378:metabolism; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male
D019830:Adenosine-5'-(N-ethylcarboxamide); C038683:2',3'-di-O-nitro-(5'-N-ethylcarboxamido)adenosine; D005982:Glutathione Transferase; D000241:Adenosine