Disposition of a new tamibarotene prodrug in mice.
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 beta-oxidation pathway of IT-M-07000 to tamibarotene were detected in mouse plasma. It was thus shown that IT-M-07000 is probably beta-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.
Sugitani
Megumi
M
Department of Clinical Pharmacokinetics, Hoshi University, Japan. sugiyama@hoshi.ac.jp
Abe
Rieko
R
Ikarashi
Nobutomo
N
Ito
Kiyomi
K
Muratake
Hideaki
H
Shudo
Koichi
K
Sugiyama
Kiyoshi
K
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism*; D019540:Area Under Curve; D001565:Benzoates / Q000097:blood / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D010666:Phenylpropionates / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000097:blood / Q000378:metabolism*
D000970:Antineoplastic Agents; D001565:Benzoates; C548358:IT-M-07000; D010666:Phenylpropionates; D011355:Prodrugs; D013764:Tetrahydronaphthalenes; C061133:tamibarotene