title: 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 (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.
authors: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey 08543, USA. zhang4422@gmail.com
authors: Donglu
authors: D
authors: Zhang
authors: Kan
authors: K
authors: He
authors: John J
authors: JJ
authors: Herbst
authors: Janet
authors: J
authors: Kolb
authors: Wilson
authors: W
authors: Shou
authors: Lifei
authors: L
authors: Wang
authors: Praveen V
authors: PV
authors: Balimane
authors: Yong-Hae
authors: YH
authors: Han
authors: Jinping
authors: J
authors: Gan
authors: Charles E
authors: CE
authors: Frost
authors: W Griffith
authors: WG
authors: Humphreys
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells / Q000378:metabolism; D002461:Cell Line, Transformed; D002463:Cell Membrane Permeability / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004077:Digoxin / Q000493:pharmacokinetics; D054659:Diketopiperazines; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics*; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D009288:Naproxen / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles / Q000493:pharmacokinetics*; D011728:Pyridones / Q000493:pharmacokinetics*; D051381:Rats
chemical_list: C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D054659:Diketopiperazines; D005343:Fibrinolytic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D009363:Neoplasm Proteins; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D009288:Naproxen; D004077:Digoxin; D016572:Cyclosporine; D000241:Adenosine; D007654:Ketoconazole