Abstract
The studies reported here were conducted to investigate the transport characteristics of apixaban and to understand the impact of transporters on apixaban distribution and disposition. In human P-gp and BCRP-cDNA transfected cell monolayers as well as Caco-2 cell monolayers, the apparent efflux ratio of basolateral to apical (PcB-A) versus apical to basolateral permeability (PcA-B) of apixaban was >10. The P-gp and BCRP-facilitated transport of apixaban was concentration- and time-dependent and did not show saturation over a wide range of concentrations (1-100 μM). The efflux transport of apixaban was also demonstrated by the lower mucosal to serosal permeability than that of the serosal to mucosal direction in the isolated rat jejunum segments. Apixaban did not inhibit digoxin transport in Caco-2 cells. Ketoconazole decreased the P-gp-mediated apixaban efflux in Caco-2 and the P-gp-cDNA transfected cell monolayers, but did not affect the apixaban efflux to a meaningful extent in the BCRP-cDNA transfected cell monolayers. Co-incubation of a P-gp inhibitor (ketoconazole or cyclosporin A) and a BCRP inhibitor (Ko134) provided more complete inhibition of apixaban efflux in Caco-2 cells than separate inhibition by individual inhibitors. Naproxen inhibited apixaban efflux in Caco-2 cells, but showed only a minimal effect on apixaban transport in the BCRP-transfected cells. Naproxen was the first NSAID that was demonstrated as a weak P-gp inhibitor. These results demonstrate that apixaban is a substrate for efflux transporters P-gp and BCRP, which can help explain its low brain penetration, low fetus exposures, and milk excretion in rats.
- Received November 21, 2012.
- Accepted January 28, 2013.
- The American Society for Pharmacology and Experimental Therapeutics