P-gp and taxanes.

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In the past years, the development of oral formulations of the taxane anticancer drugs paclitaxel (Taxol®) and docetaxel (Taxotere®) has been the focus of preclinical and clinical research in our groups. A major limitation in the concept of oral administration of paclitaxel and docetaxel is their low oral availability [1]. Paclitaxel and docetaxel have poor aqueous solubility and upon oral administration, intestinal uptake is seriously hampered by drug efflux through the active efflux transporter P-glycoprotein (P-gp/MDR1/ABCB1) and by drug metabolism via Cytochrome P450 (CYP) 3A [2,3]. Several studies by our groups have shown that the oral bioavailability of paclitaxel and docetaxel can be enhanced by 1) oral administration of a solid dispersion of these taxanes [4], and 2) combining taxanes with P-gp inhibitors or CYP3A4 inhibitors to reduce intestinal and hepatic drug efflux transport and drug metabolism [1]. Importantly, since P-gp is not only expressed in tissues like intestine, liver, and kidney, but also at the blood-brain barrier (BBB) where it keeps its substrates out of the brain [5], co-administration of orally administered taxanes with P-gp inhibitors might also result in increased brain penetration of the taxanes.