Characterization of the major metabolite of sampangine in rats.
Sampangine (1) is a plant-derived antifungal copyrine alkaloid extracted from the stem bark of Cananga odorata. Although it possesses potent in vitro antifungal activity, 1 is devoid of significant and reproducible in vivo activity in a mouse model of cryptococcosis. Speculating that the lack of in vivo activity could be due to metabolism, a study was undertaken to begin to develop an understanding of the pharmacokinetics, and particularly metabolism of 1. Following intraperitoneal administration of 1 to rats, urine was collected, extracted, and chromatographed over a reversed-phase C(18) silica column to yield the major metabolite, SAM MM1 (2), which was identified by NMR and MS to be an O-glucuronide conjugate of sampangine. In addition, two other unstable, structurally uncharacterized minor metabolites were produced, as evidenced by HPLC analysis. Evaluation of the antifungal and antibacterial activities of 2 showed it to have remarkable in vitro activity against Cryptococcus neoformans.
Orabi
K Y
KY
Department of Pharmacognosy, Department of Pharmacology, and National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, 38677, USA.
Walker
L A
LA
Clark
A M
AM
Hufford
C D
CD
D000470:Alkaloids / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003453:Cryptococcosis / Q000188:drug therapy; D003455:Cryptococcus neoformans / Q000187:drug effects; D020719:Glucuronides; D006576:Heterocyclic Compounds, 4 or More Rings; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008826:Microbial Sensitivity Tests; D009287:Naphthyridines; D051381:Rats; D017208:Rats, Wistar
D000470:Alkaloids; D000935:Antifungal Agents; D020719:Glucuronides; D006576:Heterocyclic Compounds, 4 or More Rings; D009287:Naphthyridines; C121572:sampangine