Received for publication June 9, 2008.
Revised September 9, 2008.
Accepted for publication September 10, 2008.

Lacteal Excretion, Fetal and Maternal Tissue Distribution of Dasatinib in Rats

Abstract

Dasatinib (SPRYCEL®, BMS-354825) is a potent and broad spectrum kinase inhibitor, used for the treatment of chronic myeloid leukemia and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Dasatinib exhibited extensive lacteal excretion in Sprague-Dawley rats following a single oral dose of [¹⁴C]-dasatinib (10 mg/kg, 300 µCi/kg). Radioactivity was detected through 72 hours post-dose, with a milk/plasma AUC0-inf ratio of approximately 25. The majority of the total radioactivity in milk was attributed to unchanged dasatinib. Following a single dose of [¹⁴C]-dasatinib to pregnant Sprague-Dawley rats at gestation day 18, radioactivity was extensively distributed in maternal tissues. The radioactivity detected by tissue excision or quantitative whole body autoradiography was highest in adrenal gland, mammary tissue, lungs, kidneys, liver and placenta. Compared with maternal tissues, a relatively low level of radioactivity was detected in fetal tissues. The concentrations of dasatinib-equivalents in fetal liver and kidneys were <13% of the respective maternal organs. The C_max of the dasatinib-equivalents in fetal blood was approximately 39% of that in maternal blood, however, the AUC values were comparable. Fetal brain/blood ratios of C_max and AUC0-inf were approximately 1.58 and 1.48, respectively, which were much greater than the maternal ratios of 0.12 and 0.13. In summary, dasatinib is extensively distributed in maternal tissues and secreted into milk, but its penetration into the adult brain was limited. Transporters may be involved in mediating dasatinib distribution in the adult rat, while in the fetus, tissue and blood exposures were similar, suggesting that distribution in the fetus is predominantly medited by diffusion.

Key words: active transport, blood-brain barrier, distribution, drug distribution, drug secretion, reproductive toxicology