In Vitro Interactions between a Potential Muscle Relaxant E2101 and Human Cytochromes P450

• Published in: Drug metabolism and disposition Vol. 30; no. 7; pp. 805 - 813
• Main Authors: ZHANG, Zhi-Yi, KING, Belinda M, MOLLOVA, Nevena N, WONG, Y. Nancy
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.07.2002
• Subjects: Acetamides - chemistry; Acetamides - metabolism; Biological and medical sciences; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - metabolism; Enzyme Induction; Enzyme Inhibitors - metabolism; Humans; Isoenzymes - metabolism; Medical sciences; Microsomes, Liver - enzymology; Muscle; Muscle Relaxants, Central - chemistry; Muscle Relaxants, Central - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Piperidines - chemistry; Piperidines - metabolism; Serotonin Antagonists - chemistry; Serotonin Antagonists - metabolism; Serotoninergic system; Human; Digestive system; Muscle relaxant; Metabolite; Cytochrome P450; Liver; Enzyme inhibitor; Molecular interaction; Serotonine receptor; Microsome; Metabolism; In vitro; Antagonist
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.30.7.805

E2101 or N -methyl-[1-[1-(2-fluorophenethyl)piperidine-4-yl]-1 H -indol-6-yl] acetamide, an antagonist of 5-hydroxytryptamine receptor subtypes 1A and 2, is currently under development for the potential treatment of skeletal muscle associated spasticity. Here we characterized the in vitro metabolism of E2101 using human liver enzymes including human liver microsomal preparations, human liver S9 fractions, and individual forms of recombinant cytochromes P450 (P450s). Our results showed that E2101 was metabolized by P450s to form monohydroxylated (M1 and M2), dihydroxylated (M3), and N -dealkylated metabolites (M4). The structures of these major microsomal metabolites were proposed based on LC/MS/MS analyses. All four metabolites, M1–M4, were formed by CYP3A4. Metabolites, M1, M2, and M4, were also formed by CYP2C19 and M2 and M3 by CYP2D6. The potential P450 inhibition and induction of E2101 were also evaluated. E2101 was determined to be a competitive inhibitor of CYP2C19 and CYP2D6 with K i of 15 and 48 μM, respectively, as determined by both Dixon plots and simultaneously nonlinear regression analyses. Induction of major P450 expression was not detected immunochemically after 72-h exposure to 10 or 50 μM E2101 in primary hepatocyte cultures obtained from three subjects. Taken together, E2101 is expected to metabolically interact with major human P450 enzymes including CYP2C19, CYP2D6, and CYP3A4, and a low risk of drug-drug interaction would be anticipated in clinical studies.