P-gp and taxanes

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. Enhanced brain penetration of anticancer drugs due to P-gp inhibition at the BBB can be a double-edged sword: on the one hand, for specifically targeted anticancer drugs, including many tyrosine kinase inhibitors (TKIs), with a low chance of causing problems in the central nervous system (CNS), it may comparatively safely enhance efficacy of the drugs against brain tumor parts or brain (micro)metastases that are positioned behind a functionally intact BBB. On the other hand, for potentially neurotoxic cytotoxins such as the taxanes, there is a risk of disrupting brain functions upon increased CNS penetration, which may thus be undesirable. Our recent study was set up in part to assess the risk of enhancing taxane brain penetration when applying oral taxane administration regimens. We first examined whether we could substantially increase the oral availability of taxanes (at 10 mg/kg) in mice by simultaneous inhibition of P-gp and CYP3A4 using oral co-administration of elacridar (25 mg/kg) and ritonavir (12.5 mg/kg), and to what extent this would affect P-gp transport at the blood-brain barrier [6]. Comparison of the taxane plasma levels obtained in our study with previously reported data obtained from oral administration of taxanes to knockout mice [2,3] showed that orally administered elacridar and ritonavir at comparatively low doses could completely (for paclitaxel), …