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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Distribution of tamoxifen and its metabolites in rat and human tissues during steady-state treatment.

A procedure for the extraction of tamoxifen and metabolites from various rat and human tissues was developed and verified. With this method, we determined the drug and metabolite concentrations during one dosing interval in various tissues (brain, fat, liver, heart, lung, kidney, uterus, and testes) of rats given tamoxifen once daily for 3 or 14 days, and in various normal and malignant tissues obtained during surgery or at autopsy from patients with breast cancer treated with tamoxifen. In the rat, the concentrations of tamoxifen and metabolites in most tissues were 8- to 70-fold higher than in serum. The highest levels were observed in lung and liver; substantial amounts were also recovered from kidney and fat. Fluctuations of metabolites and tamoxifen content in most tissues were observed during one dosing interval, corresponding to a ratio of 4:8 between Cmax and Cmin, except in fat and testicular tissues, where the drug concentrations were relatively stable. In addition to tamoxifen, N-desmethyltamoxifen, followed by 4-hydroxytamoxifen, 4-hydroxy-N-desmethyltamoxifen, and N-desdimethyltamoxifen, were abundant in most tissues. In contrast, adipose tissue contained only small amounts of these metabolites. The concentrations of tamoxifen and metabolites found in human normal and malignant tissues confirmed and extended the conclusions made in the experiments with rats. In humans, levels were 10- to 60-fold higher in tissues than in serum, and relatively high concentrations were detected in liver and lung. Additionally, pancreas, pancreatic tumor, and brain metastases from breast cancer and primary breast cancer retained large amounts of drug. Again, the amounts of demethylated and hydroxylated metabolites were high in most tissues, except in fat. Tamoxifen and some metabolites were also present in specimens of skin and bone tissue. In one patient, significant amounts of drugs could be detected in lung, heart, ovary, and intestinal wall 14 months after withdrawal of tamoxifen, demonstrating efficient retention and slow washout of these compounds in human tissue.[1]

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