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KMID : 0370220160600060297
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Yakhak Hoeji
2016 Volume.60 No. 6 p.297 ~ p.303
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Metabolic Characterization of Omecamtiv Mecarbil in Liver Microsomes and in Mice
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Jeon Jang-Su
Ryu Chang-Seon
Kim Sang-Kyum
Kim Bong-Hee
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Abstract
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Omecamtiv mecarbil is a cardiac-specific myosin activator for developing the treatment of heart failure. The purpose of this study was to determine the metabolic stability and cytochrome P450 (CYP) inhibitory potential of omecamtiv mecarbil, using human liver microsomes (HLM) to characterize its metabolic properties. In addition, pharmacokinetic analysis was performed in mice treated intravenously (1 mg/kg) or orally (2 mg/kg) with omecamtiv mecarbil for comparison with our in vitro results. The half-life of omecamtiv mecarbil in HLM incubated with NADPH plus UDPGA was 83.1 min. In pharmacokinetic study, omecamtiv mecarbil was low systemic clearance (0.6±0.1 L/hr/kg) and 51.1% of oral bioavailability. Among CYP isoforms, CYP2C8 activity was selectively inhibited by omecamtiv mecarbil with an IC50 value of 5.98 μM, comparable for that of quercetin, a positive control inhibitor for CYP2C8. These results suggest that omecamtiv mecarbil can be used as a selective CYP2C8 inhibitor.
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KEYWORD
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Drug metabolism, Pharmacokinetics, Omecamtiv mecarbil, Drug interaction
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