Association of tamoxifen biliary excretion rate with prior tamoxifen exposure and increased mdr1b expression

ATPase transporter proteins are commonly found in the hepatocyte canalicula r membrane. Some of these, in particular the multidrug resistance (mdr1b) g ene, have been previously demonstrated to be inducible genes. In this study , we found that tamoxifen induced expression of the mdr1b gene in the liver up to 40-fold after 14 days' exposure to tamoxifen in the diet at a concen tration of 420 ppm. As tamoxifen and its metabolites are primarily excreted into the bile, we investigated if the increased expression of mdr1b in the liver following tamoxifen exposure had any effect on its excretion in rats . We found that the excretion of tamoxifen and its metabolites into bile wa s increased from 8 +/- 1% to 51 +/- 18% (mean +/- SD) of an administered do se of 180 nmol/kg over a collection period of 3 hr in rats that had receive d tamoxifen (35 mg/kg) orally for 12 days (plus a 3-day rest) prior to the experiment. These data suggest that prolonged treatment with tamoxifen may result in lower serum and tumour concentrations, due to a self-mediated enh ancement of excretion via mdr1b gene-encoded P-glycoprotein. This may have implications for other drugs sharing the same route of excretion and co-adm inistered with tamoxifen. (C) 2000 Elsevier Science Inc.