title: Identification of cytochrome P-450 isoform(s) responsible for the metabolism of pimobendan in human liver microsomes.
abstract: Pimobendan, 4, 5-dihydro-6-(2-(4-methoxyphenyl)-1H-benzimidazol-5-yl)-5-methyl-3( 2-H )-pyridazinone, is a new inotropic drug that augments Ca(2+) sensitivity and inhibits phosphodiesterase in cardiomyocytes. Pimobendan is well absorbed after oral administration and is metabolized in the liver to the O-demethyl metabolite, which is also active. This study was conducted to identify the cytochrome P-450 (CYP) isoform(s) responsible for the pimobendan O-demethylation in human liver microsomes. Pimobendan O-demethylase activity in human liver microsomes was significantly correlated with phenacetin O-deethylase activity. CYP1A2 antibody and specific inhibitors of CYP1A2 strongly inhibited the metabolism of pimobendan. CYP1A2 was the only one of 10 recombinant human CYP isoforms tested that catalyzed pimobendan O-demethylation at the substrate concentration of 1 microM. At a high substrate concentration (100 microM), recombinant CYP3A4 also catalyzed the reaction, and antibody to CYP3A4 partially inhibited the activity in human liver microsomes. The contribution of CYP1A2 to pimobendan O-demethylation in human liver microsomes varied in the range of 18 to 76%, whereas CYP3A4 accounted for less than 10%, as calculated using the relative activity factor method. We conclude that CYP1A2 is one of the major enzymes responsible for the O-demethylation of pimobendan and CYP3A may make a minor contribution at clinically relevant concentrations of the drug.
authors.affiliation: Division of Pharmacy, University Hospital, Japan.
authors.forename: S i
authors.initials: Si
authors.lastname: Kuriya
authors.forename: S
authors.initials: S
authors.lastname: Ohmori
authors.forename: M
authors.initials: M
authors.lastname: Hino
authors.forename: I
authors.initials: I
authors.lastname: Ishii
authors.forename: H
authors.initials: H
authors.lastname: Nakamura
authors.forename: C
authors.initials: C
authors.lastname: Senda
authors.forename: T
authors.initials: T
authors.lastname: Igarashi
authors.forename: M
authors.initials: M
authors.lastname: Kiuchi
authors.forename: M
authors.initials: M
authors.lastname: Kitada
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002316:Cardiotonic Agents / Q000493:pharmacokinetics*; D019388:Cytochrome P-450 CYP1A2 / Q000302:isolation & purification / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000302:isolation & purification* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000493:pharmacokinetics*; D020033:Protein Isoforms / Q000302:isolation & purification; D011724:Pyridazines / Q000493:pharmacokinetics*; D014665:Vasodilator Agents / Q000493:pharmacokinetics*
chemical_list: D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D020033:Protein Isoforms; D011724:Pyridazines; D014665:Vasodilator Agents; C041648:pimobendan; D003577:Cytochrome P-450 Enzyme System; D019388:Cytochrome P-450 CYP1A2