title: Metoclopramide is metabolized by CYP2D6 and is a reversible inhibitor, but not inactivator, of CYP2D6.
abstract: 1. Metoclopramide is a widely used clinical drug in a variety of medical settings with rare acute dystonic events reported. The aim of this study was to assess a previous report of inactivation of CYP2D6 by metoclopramide, to determine the contribution of various CYPs to metoclopramide metabolism, and to identify the mono-oxygenated products of metoclopramide metabolism. 2. Metoclopramide interacted with CYP2D6 with Type I binding and a Ks value of 9.56 ± 1.09 µM. CYP2D6 was the major metabolizer of metoclopramide and the two major products were N-deethylation of the diethyl amine and N-hydroxylation on the phenyl ring amine. CYPs 1A2, 2C9, 2C19, and 3A4 also metabolized metoclopramide. 3. While reversible inhibition of CYP2D6 was noted, CYP2D6 inactivation by metoclopramide was not observed under conditions of varying concentration or varying time using Supersomes(TM) or pooled human liver microsomes. 4. The major metabolites of metoclopramide were N-hydroxylation and N-deethylation formed most efficiently by CYP2D6 but also formed by all CYPs examined. Also, while metoclopramide is metabolized primarily by CYP2D6, it is not a mechanism-based inactivator of CYP2D6 in vitro.
authors.affiliation: Department of Chemistry, Kalamazoo College, Kalamazoo, MI 49006 USA.
authors.forename: Mara R
authors.initials: MR
authors.lastname: Livezey
authors.affiliation: Department of Chemistry, Kalamazoo College, Kalamazoo, MI 49006 USA.
authors.forename: Erran D
authors.initials: ED
authors.lastname: Briggs
authors.affiliation: Department of Chemistry, Kalamazoo College, Kalamazoo, MI 49006 USA.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Bolles
authors.affiliation: Department of Chemistry, Kalamazoo College, Kalamazoo, MI 49006 USA.
authors.forename: Leslie D
authors.initials: LD
authors.lastname: Nagy
authors.affiliation: Department of Chemistry, Kalamazoo College, Kalamazoo, MI 49006 USA.
authors.forename: Rina
authors.initials: R
authors.lastname: Fujiwara
authors.affiliation: Department of Chemistry, Kalamazoo College, Kalamazoo, MI 49006 USA.
authors.forename: Laura Lowe
authors.initials: LL
authors.lastname: Furge
mesh_terms: D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D018492:Dopamine Antagonists / Q000737:chemistry; D006801:Humans; D019811:Hydroxylamine / Q000737:chemistry; D006900:Hydroxylation; D007700:Kinetics; D008024:Ligands; D008099:Liver / Q000187:drug effects; D008787:Metoclopramide / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D018492:Dopamine Antagonists; D008024:Ligands; D011994:Recombinant Proteins; D019811:Hydroxylamine; D019389:Cytochrome P-450 CYP2D6; D008787:Metoclopramide