Isolation of a novel morphinan 3-O-diglucuronide metabolite from dog urine.

Following oral administration of the narcotic antagonist nalmefene [17-(cyclopropylmethyl)-4,5 alpha-epoxy-6-methylenemorphinan-3,14-diol] labeled with 14C to the dog, approximately 50% of the dose was excreted in the urine as a highly polar water-soluble conjugate. Although this major metabolite could be hydrolyzed with beta-glucuronidase to yield nalmefene, the intact conjugate was chromatographically more polar on reversed-phase high-performance liquid chromatography (HPLC) than authentic nalmefene 3-O-glucuronide. Milligram quantities of the metabolite were subsequently isolated and subjected to fast atom bombardment (FAB) mass spectral and nuclear magnetic resonance (NMR) analyses.

Evidence for the delivery of narcotic antagonists to the colon as their glucuronide conjugates.

Morphine-dependent rats were used to evaluate the effects of the narcotic antagonists, naloxone and nalmefene, and their glucuronide conjugates on the gastrointestinal tract and various parameters of brain-mediated withdrawal. When administered s.c.

Cardiovascular effects of KM-13, a new, orally effective, cardiotonic sympathomimetic amine.

Dobutamine's chemical structure was modified to make it orally effective, while its pharmacological profile was preserved. Testing on anesthetized dogs showed that replacement of the para hydroxyl group with carboxyamide at the phenyl end of the molecule increased inotropic potency threefold, but it introduced pressor activity that spoiled the inotropic selective profile of dobutamine. However, shifting carboxyamide to the meta position avoided pressor activity and further enhanced inotropic potency to nine times that of dobutamine.