Biotransformation of Molsidomine (N-Ethoxycarbonyl-3-morpholinosydnonimine), a New Anti-anginal Agent, in Rats

Abstract

1. After oral administration of [¹⁴C]N-ethoxycarbonyl-3-morpholinosydnon-imine (molsidomine) to rats, 85.0% of the ingested radioactivity was excreted in urine in 24 h. Metabolites found in the urine were molsidomine (0.6% of urinary radioactivity), 3-morpholinosydnonimine (compound A, 8.4%) and N-cyanomethylenaminomorpholine (compound C, 15%). About 48% of urinary radioactivity was accounted for by approximately equal amounts of the two weakly acidic metabolites N-cyanomethylenaminomorpholine-2-one (compound D) and N-cyanomethylenamino-N-(2-hydroxyethyl)-glycine (compound E).

2. In 24 h after intraduodenal injection of [¹⁴C]molsidomine to rats, 13.3% of the radioactivity was excreted in the gastric juice as molsidomine (95%) and compound C (4.8%). Much of the molsidomine in the gastric juice was present a polar, conjugate-like compound, which on purification by t.l.c. was converted to the parent drug.

3. After intravenous injection of [¹⁴C]molsidomine to rats, the blood level declined biphasically with half-lives of 24 and 280 min, this decline being associated with a rapid appearance of the metabolites. In contrast, the blood molsidomine level did not decline after intravenous injection in totally hepa-tectomized rats, and much lower levels of the metabolites were detected. In vitro metabolic studies using blood and tissue slices indicated that the drug was metabolized only in the liver among tissues tested.

4. A possible metabolic pathway of molsidomine via compound A and N-nitroso-N-morpholinoaminoacetonitrile (compound B), both of which have hypotensive action, is proposed. The pharmacological activity of molsidomine is discussed in relation to its metabolism.