Apixaban was metabolized very gradually in liver microsomes and hepatocytes, despite the fact that O-demethyl apixaban was formed in hepatocytes from all species, although O-demethyl apixaban sulfate was detected in rat, monkey and human hepatocytes only. No metabolites were formed by human kidney microsomes or human intestinal S9 fraction. Similarly, no glutathione adduct of apixaban was detected in microsomes or hepatocytes, indicating the formation of reactive metabolites with apixaban is unlikely. The in vitro metabolism of apixaban was mainly mediated by CYP3A4/5, with reasonably small contributions from CYP1A2 and CYP2J2 towards the formation of O-demethyl apixaban. Furthermore, very low amounts of O-demethyl apixaban formation had been catalyzed by CYP2C8, CYP2C9 and CYP2C19 .
The sulfation of O-demethyl apixaban to type O-demethyl apixaban sulfate, just about the most abundant circulating metabolite in humans, was principally pd173074 selleck chemicals catalyzed from the sulfotransferase SULT1A1 . In animals acquiring apixaban, 8.7% to 47% with the recovered radioactivity appeared within the urine as apixaban, indicating that renal clearance was a route of apixaban elimination . Biliary clearance was a minor apixaban elimination pathway . In bile duct-cannulated rats, 12% of an IV dose was recovered in bile as apixaban . Apixaban was recovered within the feces soon after IV administration to bile ductcannulated rats, suggesting that intestinal secretion of apixaban also occurred. Metabolic clearance was much less necessary than, or of equivalent magnitude, to non-metabolic clearance in rats, canines and people. Almost all of the recovery of metabolites was through the feces.
In summary, the elimination of apixaban entails many pathways, which include hepatic metabolic process, renal excretion and intestinal/biliary Proteasome Inhibitors selleck secretion, just about every accountable for elimination of roughly one-third of dose. Apixaban is known as a substrate for CYP3A4/5, BCRP and P-gp . Co-administration of medicines that modulate CYP3A4/5, P-gp or BCRP actions could thus probably affect the disposition of apixaban. Provided that apixaban has many routes of elimination and an oral bioavailability of around 50% , any such drug?drug interaction effects are very likely to be of comparatively minimal magnitude.
This hypothesis is supported through the final results of clinical drug?drug interaction studies that present that increases in apixaban exposure are around twofold following coadministration that has a powerful inhibitor of the two CYP3A4 and P-gp , despite the fact that an around 50% reduce in apixaban publicity is observed soon after coadministration of apixaban using a sturdy inducer of the two CYP3A4 and P-gp . The prospective of apixaban to inhibit or induce CYP is minimum, suggesting that apixaban is unlikely to impact the metabolism of co-administered prescription drugs which have been dependent on CYP-mediated clearance.