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.