title: Normal-phase liquid chromatography-particle-beam mass spectrometry in drug metabolism studies of the dopamine receptor antagonist Odapipam and the muscarine M1 receptor agonist Xanomeline.
abstract: 1. The metabolism of Odapipam has been studied with phenobarbital-induced rat liver microsomes, followed by analysis with normal-phase hplc in combination with particle-beam mass spectrometry. 2. During the incubation of Odapipam, five different metabolites were formed. The EI+ mass 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 moiety. 3. The intrinsic hepatic extraction ratio and metabolism of Xanomeline 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 microM. 4. Analysis of the perfusate by normal-phase hplc and particle-beam mass spectrometry showed the formation of at least six metabolites. The EI+ mass spectrum of the metabolites indicated the formation of omega-3 hydroxy-, omega-2 hydroxy-, omega-1 hydroxy-, omega-1 keto-Xanomeline in addition to omega-1 hydroxy-N-desmethyl-Xanomeline and an N-oxide of Xanomeline. 5. The results show that normal-phase hplc based on silica material is superior to reversed-phase-based systems in terms of selectivity. Furthermore, the use of non-aqueous solvents in combination with particle-beam mass spectrometry is advantageous compared with reversed-phase hplc since changing between different solvents in normal-phase hplc results only in minor changes in the particle-beam interface parameters such as nebulizer position, helium pressure and interface temperature.
authors.affiliation: Department of Drug Metabolism, Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark.
authors.forename: J V
authors.initials: JV
authors.lastname: Andersen
authors.forename: K T
authors.initials: KT
authors.lastname: Hansen
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000378:metabolism*; D001572:Benzofurans / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D018492:Dopamine Antagonists / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D018721:Muscarinic Agonists / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013830:Thiadiazoles / Q000378:metabolism*
chemical_list: D001552:Benzazepines; D001572:Benzofurans; D018492:Dopamine Antagonists; D018721:Muscarinic Agonists; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D013830:Thiadiazoles; C075357:odapipam; C075257:xanomeline