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Characterization of Efflux Transporters Involved in Distribution and Disposition of Apixaban
Author(s) -
Zhang Donglu,
Herbst John J,
Kolb Janet,
Wang Lifei,
Shou Wilson,
Balimane Praveen,
He Kan,
Frost Charles,
Humphreys w Griffith
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.891.2
Subject(s) - apixaban , efflux , abcg2 , pharmacology , chemistry , transporter , caco 2 , apical membrane , biochemistry , atp binding cassette transporter , cell , biology , medicine , membrane , rivaroxaban , warfarin , gene , atrial fibrillation
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 P‐gp and BCRP‐cDNA transfected cell monolayers, as well as Caco‐2 cell monolayers, the apparent efflux ratio of basolateral to apical (Pc B‐A ) versus apical to basolateral permeability (Pc A‐B ) of apixaban was 10–38 compared to the apixaban efflux ratios of 1–4 in control cells. 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 P‐gp‐cDNA transfected cell monolayers, but did not affect the apixaban efflux to a meaningful extent in 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. These results demonstrate that apixaban is a substrate for efflux transporters P‐gp and BCRP, which helps explain the observed disposition characteristics of the drug in rat studies that include its low brain penetration, low fetal exposure, and extensive excretion into milk.