PT - JOURNAL ARTICLE AU - Donglu Zhang AU - Kan He AU - John J. Herbst AU - Janet Kolb AU - Wilson Shou AU - Lifei Wang AU - Praveen V. Balimane AU - Yong-Hae Han AU - Jinping Gan AU - Charles E. Frost AU - W. Griffith Humphreys TI - Characterization of Efflux Transporters Involved in Distribution and Disposition of Apixaban AID - 10.1124/dmd.112.050260 DP - 2013 Apr 01 TA - Drug Metabolism and Disposition PG - 827--835 VI - 41 IP - 4 4099 - http://dmd.aspetjournals.org/content/41/4/827.short 4100 - http://dmd.aspetjournals.org/content/41/4/827.full SO - Drug Metab Dispos2013 Apr 01; 41 AB - The studies reported here were conducted to investigate the transport characteristics of apixaban (1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide) and to understand the impact of transporters on apixaban distribution and disposition. In human permeability glycoprotein (P-gp)- and breast cancer resistance protein (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 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. Coincubation 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 nonsteroidal antiinflammatory drug 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, and low fetal exposures and high milk excretion in rats.