Abstract

In vitro metabolism of panomifene (E-1,2-diphenyl-1-[4-(2-(2-hydroxyethyl-amino)-ethoxy)-phenyl]-3,3,3-trifluoropropene), a novel antiestrogen against hormone dependent tumors, has been investigated using liver microsomes from mouse, rat, dog, and human. Hydroxylation and side chain modifications were the routes of panomifene metabolism. Microsomal biotransformation showed some qualitative similarities, but several differences were observed in the metabolic profiles of the four species tested. Seven metabolites were detected in the incubation mixtures analyzed by thin layer chromatography and autoradiography, although there was only one produced by all species that had lost the side chain. Among the side chain shortened metabolites, the compound that had lost the hydroxyethyl-amino group was formed by the microsomal system of rodents, whereas the one that had lost the hydroxyethyl group was detected in the incubation mixtures with rat, dog, and human microsomes. Three metabolites (M1, M3, and M4) were produced exclusively by the dog. The structure of M3 was identified by mass spectroscopy as 4-hydroxy-panomifene. Furthermore, human liver microsomes formed a metabolite (M8) that was not detectable in the mixtures with mouse, rat, or dog microsomes. Its structure is suspected to be an oxidized form of panomifene with a double bound in the side chain.

The structure of panomifene is analogous to tamoxifen, an antiestrogen currently used as a therapeutic agent against breast cancer, and there are some similar routes in their metabolism. The main difference is that the rate of tamoxifen biotransformation seems faster than that of panomifene. On the other hand, 4-hydroxy-panomifene is produced by only dog, while 4-hydroxylated derivative is one of the main metabolites of tamoxifen that has potent antiestrogenic activity and is considered to be responsible for the formation of DNA-adducts.