Regioselectivity and stereoselectivity of the metabolism of the chiral quinolizidine alkaloids sparteine and pachycarpine in the rat.
1. The metabolism of (-)-sparteine and (+)-sparteine (pachycarpine) was investigated in male Sprague-Dawley rats by g.l.c.-mass spectrometry, and 13C- and 2H-n.m.r. spectroscopy. The structure of the major metabolite of (-)-sparteine was confirmed to be 2,3-didehydrosparteine by g.l.c.-mass spectrometry after alkaline sample work-up. 2H-n.m.r. spectroscopy showed that this metabolite exhibits the structure of the carbinolamine (2S)-hydroxysparteine in aqueous solution of neutral pH. No other metabolites with an enamine structure were observed by g.l.c.-mass spectrometry and 13C-n.m.r. spectroscopy. 2. Pachycarpine is metabolized in vivo and in vitro stereoselectively to the aliphatic alcohol (4S)-hydroxypachycarpine as the main metabolite. 3. The formation of the 2,3-didehydrosparteine proceeds via stereospecific abstraction of the axial 2 beta hydrogen atom. Inhibition in vitro studied with purified rat liver microsomes demonstrated that both sparteine enantiomers are metabolized by the same cytochrome P450 isozyme. Therefore this enzyme exhibits marked substrate and product stereoselectivity for the metabolism of the two enantiomeric quinolizidine alkaloids.
Ebner
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Dr Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.
Meese
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Eichelbaum
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D000284:Administration, Oral; D000818:Animals; D002849:Chromatography, Gas; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D011190:Potassium Cyanide / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013034:Sparteine / Q000378:metabolism* / Q000493:pharmacokinetics; D013237:Stereoisomerism; D014018:Tissue Distribution
D013034:Sparteine; D003577:Cytochrome P-450 Enzyme System; D011190:Potassium Cyanide