PLASMA CONCENTRATIONS AND URINARY EXCRETION OF ISOSORBIDE DINITRATE AND ITS METABOLITES IN THE DOG

¹ Research Division, Wyeth Laboratories, Inc., Radnor, Pennsylvania

Plasma concentrations of ¹⁴C-isosorbide dinitrate (ISDN) and its metabolites were measured in dogs after administration of either a p.o. or i.v. dose of ¹⁴C-ISDN. Negligible levels of radioactivity were observed in erythrocytes. Two minutes after drug administration, ISDN plasma concentrations in p.o. dosed dogs were of those observed in i.v. dosed dogs. ISDN rapidly disappeared from plasma within 1 hour after i.v. administration and within hour after p.o. administration. The disappearance of drug after the i.v. dose coincided with a rise in mononitrate levels. A similar rise was observed in p.o. dosed dogs, but only after a 15-minute delay. The plasma also contained isosorbide. In urine, no noticeable difference was noted between dosage regimens in the resulting amounts of 5-isosorbide mononitrate, isosorbide and their polar conjugates. Since isosorbide was excreted unchanged in dog urine after a p.o. dose of ¹⁴C-isosorbide, it was concluded that the polar conjugate, isosorbide glucuronide, is a transformation product resulting from the denitration of 5-isosorbide mononitrate glucuronide.

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