PRECLINICAL ELECTROPHYSIOLOGY ASSAYS OF MITEMCINAL (GM-611), A NOVEL PROKINETIC AGENT DERIVED FROM ERYTHROMYCIN
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概要
- 論文の詳細を見る
Mitemcinal (GM-611) is a novel erythromycin-derived prokinetic agent that acts as an agonist at the motilin receptor. Erythromycin has shown QT prolongation and torsades de pointes (TdP) in humans and cisapride, a second class of prokinetic agents typified by the 5-HT_4 receptor agonist, has been terminated due to TdP. In this study an extended series of safety pharmacology protocols and evaluations have been undertaken to assess the potential risk of mitemcinal on QT prolongation or proarrhythmic effects. Mitemcinal and its metabolites, GM-577 and GM-625, inhibited the human ether-a-go-go-related gene (HERG) tail current in a concentration-dependent manner with IC_<50> values of 20.2, 41.7, and 55.0 μM, respectively. Administration of 10 mg/kg mitemcinal in anesthetized guinea pigs resulted in a slight prolongation of the monophasic action potential (MAP) duration during atrial pacing at the plasma concentration of mitemcinal 1.1 μM, with low maximum increases in MAPD_<70> (6.6%) and MAPD_<90> (4.6%) relative to vehicle. A 10-min infusion of 20 mg/kg of mitemcinal in a proarrhythmic rabbit model did not evoke TdP even when QT and corrected QT (QTc) intervals were significantly prolonged. In this study, the Cmax plasma-free concentration of mitemcinal indicates that the prolongation was more than 400-fold that of the therapeutic dose. Our findings of a wide safety margin and the absence of TdP within this margin suggest that mitemcinal may provide sufficient safety in clinical use.
- 日本トキシコロジー学会の論文
- 2007-08-17
著者
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Omura Satoshi
The Kitasato Institute, Kitasato Institute for Life Sciences and Graduate School of Infection Contro
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鈴木 雅実
Safety Assessment Dep. Fuji Gotemba Res. Laboratories Chugai Pharmaceutical Co. Ltd.
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鈴木 雅実
Safety Assessment Department Chugai Pharmaceutical Co. Ltd.
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Kato Atsuhiko
中外製薬富士御殿場研究所
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Kato Atsuhiko
Fuji-gotemba Research Laboratories Chugai Pharmaceutical Co. Ltd.
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Suzuki Masami
中外製薬富士御殿場研究所
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KIMURA Kazuya
Safety Assessment Department, Chugai Pharmaceutical Co., Ltd.
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Tabo Mitsuyasu
Safety Assessment Department Chugai Pharmaceutical Co. Ltd.
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Tabo Mitsuyasu
Safety Assessment Department Chugai Pharmaceutical Co. Ltd.:laboratory Of Pharmacology Graduate Scho
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Kimura Kazuya
Japan Pharmaceutical Manufacturers Assoc. Drug Evaluation Committee Non-clinical Evaluation Subcommi
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Kimura Kazuya
Fuji Gotemba Research Laboratories Chugai Pharmaceutical Co. Ltd.
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鈴木 雅実
Fuji Gotemba Research Laboratories Chugai Pharmaceutical Co. Ltd.
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Omura Satoshi
The Kitasato Institute
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KIMURA Kazuya
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.
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TABO Mitsuyasu
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.
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MIZOGUCHI Keiji
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.
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SUZUKI Masami
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.
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ITOH Zen
Gunma University
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TAKANASHI Hisanori
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.
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ITOH Misae
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd.
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Tabo Mitsuyasu
Fuji Gotemba Research Laboratories Chugai Pharmaceutical Co. Ltd.
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Mizoguchi Keiji
Research Compliance & Quality Assurance Coordination Fuji Gotemba Research Laboratories Chugai P
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Mizoguchi Keiji
Fuji-gotemba Research Laboratories Chugai Pharmaceutical Co. Ltd.
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Mizoguchi Keiji
Toxicology Laboratory Chugai Pharmaceutical Co. Ltd.
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Itoh Misae
Fuji Gotemba Research Laboratories Chugai Pharmaceutical Co. Ltd.
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Omura Satoshi
The Kitasato Inst.
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Kato Atsuhiko
Safety Assessment Laboratory Chugai Pharmaceutical Co. Ltd.
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Takanashi Hisanori
Fuji-gotemba Research Laboratories Chugai Pharmaceutical Co. Ltd.
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