title: Cytochrome P450 enzymes involved in the metabolic pathway of the histamine 2 (H2)-receptor antagonist roxatidine acetate by human liver microsomes.
abstract: Roxatidine acetate hydrochloride (ROX, 2-acetoxy-N-[3-[m-(1-piperidinylmethyl)phenoxy]propyl]acetamide hydrochloride, CAS 78273-80-0), a histamine 2 (H2)-receptor antagonist, has been clinically applied for the treatment of gastritis, gastric and duodenal ulcers. There is no report on the identification of the metabolic enzyme of M-1 (2-hydroxy-N-[3-[m-(1-piperidinylmethyl)phenoxy]propyl]acetamide), the pharmacologically active metabolite, in humans. In this study, the Cytochrome P450 (CYP or P450) enzymes which participate in the metabolism of ROX were identified using human liver microsomes and S9 fractions. M-1 was converted to M-4 (3-[m-(1-piperidinyl-methyl)phenoxy]propylamine) by the enzyme reaction with the S9 but not with microsomes. M-4 was further metabolized to M-5 (3-[m-(1-piperidinylmethyl)phenoxy]propanol) by microsomes. The metabolism was inhibited by coumarin and anti-CYP2A1 serum. (3-[m-(1-piperidinylmethyl)-phenoxy]propionic acid) and M-3 (m-(1-piperidinylmethyl) phenol) formation from M-5 were inhibited by quinidine and anti-CYP2D6 serum. Moreover, M-5 was converted to M-2 and M-3 by cDNA-expressed CYP2D6. In conclusion, this study shows that microsomal enzymes do not participate in the clearance of the active metabolite M-1, CYP2A6 primarily catalyzes M-5 formation from M-4, and CYP2D6 primarily catalyzes M-2 and M-3 formation from M-5 in humans.
authors.affiliation: Pharmacokinetics Research Department, Teikoku Hormone Mfg. Co., Ltd., Kanagawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sasaki
authors.forename: M
authors.initials: M
authors.lastname: Nakayama
authors.forename: S
authors.initials: S
authors.lastname: Numazawa
authors.forename: T
authors.initials: T
authors.lastname: Oguro
authors.forename: S
authors.initials: S
authors.lastname: Honma
authors.forename: S
authors.initials: S
authors.lastname: Iwamura
authors.forename: K
authors.initials: K
authors.lastname: Tsukamoto
authors.forename: T
authors.initials: T
authors.lastname: Yoshida
mesh_terms: D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008208:Lymphatic System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010880:Piperidines / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006635:Histamine H2 Antagonists; D007527:Isoenzymes; D010880:Piperidines; D003577:Cytochrome P-450 Enzyme System; C053742:roxatidine acetate