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.
Footnotes
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Send reprint requests to: Shigeru Ohmori, Ph.D., Division of Pharmacy, University Hospital, Chiba University School of Medicine, Chiba University, 1–8-1, Inohana, Chuo-ku Chiba 260-8677, Japan.
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↵1 These authors contributed equally to this work.
- Abbreviations used are::
- CYP
- cytochrome P-450
- RAF
- relative activity factor
- Received May 13, 1999.
- Accepted October 4, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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