Disposition of a New Tamibarotene Prodrug in Mice

• Published in: Biological & Pharmaceutical Bulletin Vol. 32; no. 12; pp. 1997 - 2001
• Main Authors: Sugitani, Megumi, Abe, Rieko, Ikarashi, Nobutomo, Ito, Kiyomi, Muratake, Hideaki, Shudo, Koichi, Sugiyama, Kiyoshi
• Format: Journal Article
• Language: English; Japanese
• Published: Japan The Pharmaceutical Society of Japan 01.12.2009; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Animals; Antineoplastic Agents - blood; Antineoplastic Agents - metabolism; Area Under Curve; Benzoates - blood; Benzoates - metabolism; Male; Metabolic Networks and Pathways; Mice; pharmacokinetics; Phenylpropionates - metabolism; prodrug; Prodrugs - metabolism; tamibarotene; Tetrahydronaphthalenes - blood; Tetrahydronaphthalenes - metabolism; β-oxidation
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.32.1997

Recently, a new compound IT-M-07000 was designed as a prodrug of tamibarotene, one of the therapeutic agents for acute promyelocytic leukemia. In the present study, IT-M-07000 was administered to mice to investigate whether it is actually metabolized to tamibarotene. Its metabolic pathway and the utility as a tamibarotene prodrug were also evaluated. After oral administration of IT-M-07000, IT-M-07000, tamibarotene and two compounds that were supposed to be metabolic intermediates in a β-oxidation pathway of IT-M-07000 to tamibarotene were detected in mouse plasma. It was thus shown that IT-M-07000 is probably β-oxidized to tamibarotene in mice. Comparison of tamibarotene concentration profiles after oral administration of IT-M-07000 or tamibarotene showed that the plasma tamibarotene concentration increased slower and was retained stable, and the area under the plasma concentration–time curve (AUC) of tamibarotene was larger in mice administered IT-M-07000 than tamibarotene. These results indicate that IT-M-07000 is possibly useful as a prodrug of tamibarotene.