Metabolism of the 4-iodo derivative of tamoxifen by isolated rat hepatocytes. Demonstration that the iodine atom reduces metabolic conversion and identification of four metabolites.

The 4-iodo derivative of tamoxifen, which has been reported to possess improved oestrogen receptor affinity and effectiveness as an inhibitor of breast tumour cell growth in vitro, was metabolized by hepatocytes isolated from rats pretreated with phenobarbital four times more slowly than tamoxifen and there was very little formation of glucuronide conjugates. Four principal metabolites were isolated. Examination of mass spectra revealed desmethyl-4-iodotamoxifen, 4-iodotamoxifen N-oxide, and alpha-hydroxydesmethyl-4-iodotamoxifen (4-[4-[2-(methylamino)ethoxy]phenyl]-4-(4-iodophenyl)-3-phenyl-but-3- (Z)-en-2-ol). Their identification was confirmed by comparison with synthesized samples. The structure of the fourth metabolite, 4'-hydroxy-4-iodotamoxifen was revealed by 1H NMR spectroscopy. The iodophenyl moiety is thus retained in all the metabolites. The iodine atom not only blocks metabolism in its vicinity but also reduced the rate of side-chain demethylation and N-oxidation by three-fold. It can be predicted from this study that the presence of the iodine atom should give the compound a greater duration of action in vivo.