NORMAL-PHASE LIQUID-CHROMATOGRAPHY PARTICLE-BEAM MASS-SPECTROMETRY INDRUG-METABOLISM STUDIES OF THE DOPAMINE-RECEPTOR ANTAGONIST ODAPIPAM AND THE MUSCARINE M1 RECEPTOR AGONIST XANOMELINE

1. The metabolism of Odapipam has been studied with phenobarbital-indu ced rat liver microsomes, followed by analysis with normal-phase hplc in combination with particle-beam mass spectrometry. 2. During the inc ubation of Odapipam, five different metabolites were formed. The EI+ m ass spectra of the metabolites indicated the formation of N-desmethyl- Odapipam, 1-hydroxy-Odapipam, the two isomers of 3'-hydroxy-(Odapipam and a metabolite which was dehydrogenated in the dihydrobenzofuran moi ety. 3. The intrinsic hepatic extraction ratio and metabolism of Xanom eline has been studied in the perfused rat liver. Increasing the input concentration resulted in measurable concentrations of Xanomeline in the perfusate, although the extraction ratio was still > 0.9 at 140 mu M. 4. Analysis of the perfusate by normal-phase hplc and particle-bea m mass spectrometry showed the formation of at least six metabolites. The EI+ mass spectrum of the metabolites indicated the formation of om ega-3 hydroxy-, omega-2 hydroxy-, omega-1 hydroxy-, omega-1 keto-Xanom eline in addition to omega-1 hydroxy-N-desmethyl-Xanomeline and an N-o xide of Xanomeline. 5. The results show that normal-phase hplc based o n silica material is superior to reversed-phase-based systems in terms of selectivity. Furthermore, the use of non-aqueous solvents in combi nation with particle-beam mass spectrometry is advantageous compared w ith reversed-phase hplc since changing between different solvents in n ormal-phase hplc results only in minor changes in the particle-beam in terface parameters such as nebulizer position, helium pressure and int erface temperature.