Abstract
Axitinib is an inhibitor of tyrosine kinase vascular endothelin growth factor receptors 1-3. ABC and SLC transport properties of axitinib were determined in selected cellular systems. Axitinib exhibited high passive permeability in all cell lines evaluated (Papp ≥ 6 x 10-6 cm/sec). Active efflux was observed in Caco-2 cells and further evaluation in MDR1- or BCRP-transfected MDCK cells indicated that axitinib is at most only a weak substrate for P-glycoprotein (P-gp) but not breast cancer resistance protein (BCRP). Axitinib showed incomplete inhibition of P-gp-mediated transport of digoxin in Caco-2 cells and BCRP transport of topotecan in BCRP-transfected MDCK cells with IC50 values of 3 μM and 4.4 μM, respectively. Axitinib (10 mg) did not pose a risk for systemic drug interactions with P-gp or BCRP per regulatory guidance. A potential risk for drug interactions through inhibition of P-gp and BCRP in the gastrointestinal tract was identified since an axitinib dose of 10 mg divided by 250 mL was greater than 10-fold the IC50 for each transporter. However, a GastroPlusTM simulation that considered the low solubility of axitinib resulted in lower intestinal concentrations and suggested a low potential for gastrointestinal interactions with P-gp and BCRP substrates. OATP1B1 and OATP1B3 transfected HEK293 cells transported axitinib to a minor extent but uptake into suspended hepatocytes was not inhibited by rifamycin SV suggesting that high passive permeability predominates. Mouse whole-body autoradiography revealed that [14C]axitinib-equivalents showed rapid absorption and distribution to all tissues except brain. This suggested efflux transport of axitinib may occur at the mouse blood brain barrier.
- ABC transporters
- anticancer agents
- drug development
- drug efflux
- drug interactions
- hepatic uptake
- p-glycoprotein
- transporters
- The American Society for Pharmacology and Experimental Therapeutics