Characterization of Efflux Transporters Involved in Distribution and Disposition of Apixaban
- 4 February 2013
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Drug Metabolism and Disposition
- Vol. 41 (4), 827-835
- https://doi.org/10.1124/dmd.112.050260
Abstract
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.Keywords
This publication has 42 references indexed in Scilit:
- Apixaban in Patients with Atrial FibrillationThe New England Journal of Medicine, 2011
- Membrane transporters in drug developmentNature Reviews Drug Discovery, 2010
- Transplacental Pharmacokinetics of Glyburide, Rhodamine 123, and BODIPY FL Prazosin: Effect of Drug Efflux Transporters and Lipid SolubilityThe Journal of pharmacology and experimental therapeutics, 2009
- P-gp Inhibition Potential in Cell-Based Models: Which “Calculation” Method is the Most Accurate?The AAPS Journal, 2008
- Validation and application of Caco-2 assays for thein vitroevaluation of development candidate drugs as substrates or inhibitors of P-glycoprotein to support regulatory submissionsXenobiotica, 2008
- Regional levels of drug transporters along the human intestinal tract: Co-expression of ABC and SLC transporters and comparison with Caco-2 cellsEuropean Journal of Pharmaceutical Sciences, 2006
- Active transport across the human placenta: impact on drug efficacy and toxicityExpert Opinion on Drug Metabolism & Toxicology, 2006
- Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)Oncogene, 2003
- Role reversal for anticancer agents.Cancer Biology & Therapy, 2002
- Evaluation of Biocoat intestinal epithelium differentiation environment (3-day cultured Caco-2 cells) as an absorption screening model with improved productivity.Pharmaceutical Research, 1997