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. The conjugate was identified as nalmefene 3-O-beta-diglucuronide with a 1,2-beta linkage between the two glucuronic acids. It is unlikely that this novel form of conjugate is unique to nalmefene and it is probably a metabolite of other morphinans and/or similar drugs in the dog. Nalmefene 3-O-diglucuronide is not a metabolite of nalmefene in man.
Dixon
R
R
Gensia Pharmaceuticals, Inc., San Diego, California 92121.
Hsiao
J
J
Hsu
H B
HB
Smulkowski
M
M
Tze-Ming-Chan
Pramanik
B
B
Morton
J
J
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D009682:Magnetic Resonance Spectroscopy; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000378:metabolism / Q000652:urine; D011487:Protein Conformation
C059503:nalmafene 3-O-diglucuronide; D009271:Naltrexone; C038981:nalmefene