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In vivo and in vitro trimethadione oxidation activity of the liver from various animal species including mouse, hamster, rat, rabbit, dog, monkey and human

Institute of Community Medicine, University of Tsukuba, Tsukuba-Shi, Ibaraki-ken 305-8575, Japan

A Ishikawa

Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575, Japan

T Horie

Eisai Research Laboratories, Eisai Co. Ltd, Ibarakiken 300-2635, Japan

Trimethadione (TMO) has the properties required of a probe drug for the evaluation of hepatic drug-oxidizing capacity and, in this study, we have summarized the in vivo and in vitro metabolism of TMO in various animal species including mouse, hamster, rat, rabbit, dog, monkey and human. In the in vivo study, the plasma TMO level was measured after intravenous or oral (human) administration of TMO at a dose of 4 mg/kg to various animal species. The rate of TMO metabolic clearance in these animal species in vivo was in the order mouse > hamster >rat>rabbit>dog>monkey>human. In the in vitro study, species differences were observed in the cytochrome P450 (P450) content and drug-oxidizing enzyme activity. The content of P450 was monkey> mouse>dog>rabbit>hamster>rat>human. On the other hand, TMO N-demethylation was in the order mouse >hamster >rat >rabbit>dog>monkey>human. There was a good correlation between the mean total body clearance of TMO (in vivo)andthemeanTMON-demethylase activity (in vitro) (y=1.7x+0.11, r=0.965, P<0.001).

These results show that TMO is a probe agent with metabolic and pharmacokinetic characteristics making it attractive for the in vivo and in vitro characterization of metabolic activity in various animal species.

Key Words: trimethadione • dimethadione • probe drug • hepatic oxidizing capacity • cytochrome P450 • liver function test • pharmacokinetic study • species

Human & Experimental Toxicology, Vol. 18, No. 1, 12-16 (1999)
DOI: 10.1177/096032719901800102


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