@article {Kuriya73, author = {Shin-ichiro Kuriya and Shigeru Ohmori and Mayuko Hino and Itsuko Ishii and Hiroyoshi Nakamura and Chiaki Senda and Takashi Igarashi and Masahiro Kiuchi and Mitsukazu Kitada}, title = {Identification of Cytochrome P-450 Isoform(s) Responsible for the Metabolism of Pimobendan in Human Liver Microsomes}, volume = {28}, number = {1}, pages = {73--78}, year = {2000}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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 Ca2+ 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 phenacetinO-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 μM. At a high substrate concentration (100 μM), recombinant CYP3A4 also catalyzed the reaction, and antibody to CYP3A4 partially inhibited the activity in human liver microsomes. The contribution of CYP1A2 to pimobendanO-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 theO-demethylation of pimobendan and CYP3A may make a minor contribution at clinically relevant concentrations of the drug. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/28/1/73}, eprint = {https://dmd.aspetjournals.org/content/28/1/73.full.pdf}, journal = {Drug Metabolism and Disposition} }