Biotransformation of desoxypeganine by microsomal enzymes of the rabbit liver.
The biotransformation of the anticholinergic quinazoline alkaloid Desoxypeganine is studied by means of aerobic incubation with the non-induced supernatant obtained at 9000g from rabbit liver homogenates as enzyme source followed by an admixture of NADPH. The metabolites were identified by high-performance liquid chromatography, chemical ionisation mass spectrometry (LC-CI MS) and electron impact mass spectrometry (LC-EI MS) in comparison with synthetic reference compounds and typical ion fragments taken from literature data. C-oxidation of Desoxypeganine to the major metabolite Pegenone was observed as well as the hydroxylation of the alicyclic ring. The incubation mixture followed Michaelis-Menten kinetics characterised by K(m) = 5.8 x 10(-5) mol L(-1) and V(max) = 4.32 nmol Pegenone/min per mg protein or 3.37 nmol Pegenone/min per nmol CYP 450, respectively. These in vitro results demonstrate that the bioactive substance Desoxypeganine is easily oxidised to its ineffective metabolite Pegenone. This provokes a problem for correct dosage finding in formulations for the treatment of Alzheimer's disease and in the therapy of alcoholism and nicotine dependence.
Illgner
Sascha
S
Department für Pharmazie-Zentrum für Pharmaforschung, Philipps-Universität Marburg, Marbacher Weg 6, D-35057 Marburg, Germany. illgner@staff.uni-marburg.de
Matusch
Rudolf
R
D000818:Animals; D018680:Cholinergic Antagonists / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D006900:Hydroxylation; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D032443:Peganum; D011799:Quinazolines / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics*; D011817:Rabbits
D018680:Cholinergic Antagonists; D011799:Quinazolines; C499396:desoxypeganine 1; C499397:pegenone 2