title: In vitro metabolism of the analgesic bicifadine in the mouse, rat, monkey, and human.
abstract: The in vitro metabolism of [(14)C]bicifadine by hepatic microsomes and hepatocytes from mouse, rat, monkey, and human was compared using radiometric high-performance liquid chromatography and liquid chromatography/tandem mass spectrometry. Two main metabolic pathways were identified in all four species. One pathway was an NADPH-dependent pathway in which the methyl group was oxidized to form a hydroxymethyl metabolite (M2). Its formation was inhibited in human microsomes only by quinidine, a CYP2D6 inhibitor. In incubations with individual cDNA-expressed human cytochromes P450, M2 was formed only by CYP2D6 and CYP1A2, with CYP2D6 activity 6-fold greater than that of CYP1A2. M2 was oxidized further to the carboxylic acid metabolite (M3) by hepatocytes from all four species. The second major metabolic pathway was an NADPH-independent oxidation at the C2 position of the pyrrolidine ring, forming a lactam metabolite (M12). This reaction was almost completely inhibited in human hepatic microsomes and mitochondria by the monoamine oxidase (MAO)-B-specific inhibitor selegiline. Clorgyline, a specific inhibitor of MAO-A, was less effective in inhibiting M12 formation. Other metabolic pathways of variable significance among the four species included the formation of carbamoyl-O-glucuronide, hydroxymethyl lactam, and carboxyl lactam. Overall, the data indicate that the primary enzymes responsible for the primary metabolism of bicifadine in humans are MAO-B and CYP2D6.
authors: Department of Drug Metabolism, Covance Laboratories Inc, Madison, WI, USA.
authors: David A
authors: DA
authors: Erickson
authors: Stacy
authors: S
authors: Hollfelder
authors: Justin
authors: J
authors: Tenge
authors: Mark
authors: M
authors: Gohdes
authors: Jeffrey J
authors: JJ
authors: Burkhardt
authors: Philip A
authors: PA
authors: Krieter
mesh_terms: D000700:Analgesics / Q000378:metabolism*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002264:Carboxylic Acids / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003010:Clorgyline / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007769:Lactams / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D012642:Selegiline / Q000494:pharmacology; D013045:Species Specificity; D053719:Tandem Mass Spectrometry
chemical_list: D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002250:Carbon Radioisotopes; D002264:Carboxylic Acids; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D020719:Glucuronides; D007769:Lactams; D008996:Monoamine Oxidase Inhibitors; D011994:Recombinant Proteins; D012642:Selegiline; D009249:NADP; C034438:bicifadine; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D008995:Monoamine Oxidase; D011802:Quinidine; D003010:Clorgyline