Characterization of Efflux Transporters Involved in Distribution and Disposition of Apixaban

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 (Pc B-A ) versus apical-to-basolateral permeability (Pc A-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 mM). The efflux transport of apixaban was also demonstrated by the lower mucosal-to-serosal permeability than that of the serosal-tomucosal 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.

Evolving Treatments for Arterial and Venous Thrombosis

“…20,21 All of the DOACs are substrates for P-glycoprotein and potent inhibitors or inducers of P-glycoprotein can increase or decrease the plasma concentrations of the DOACs, respectively. [22][23][24][25] The DOACs are cleared through renal and extrarenal pathways. The extent of renal clearance varies and of the absorbed unchanged drug, the kidneys are responsible for clearance of 80% of dabigatran, 50% of edoxaban, 33% of rivaroxaban, and 27% of apixaban.…”

Investigating the Enteroenteric Recirculation of Apixaban, a Factor Xa Inhibitor: Administration of Activated Charcoal to Bile Duct-Cannulated Rats and Dogs Receiving an Intravenous Dose and Use of Drug Transporter Knockout Rats

“…Previous data with apixaban demonstrated that the drug was a substrate for efflux transporters P-gp and BCRP (Zhang et al, 2013). In this study, we investigated the impacts of intestinal excretion (IE) and enteroenteric recirculation (EER) as well as renal tubule recirculation (RTR) (Fig.…”

Напроксен: Нова Стратегія Зниження Серцево-Судинного Ризику Нестероїдних Протизапальних Препаратів

“…Совместное введение напроксена не оказывало влияния на фармакокинетику апиксабана: 90% доверительное среднее геометрическое соотношение для C max апик-сабана с напроксеном или без напроксена находилось в интервале эквивалентности (125 %). Было установ-лено, что отсутствовала разница между Т max или Т 1/2 апиксабана с напроксеном и без него, механизм этого взаимодействия стал результатом лучшей биодоступно-сти апиксабана с напроксеном или без [45]. Показатели ингибитора Ха фактора свертывания крови и МНО были одинаковыми при использовании апиксабана [78,79].…”