PT  - JOURNAL ARTICLE
AU  - Mohamed, Loqman A.
AU  - Kaddoumi, Amal
TI  - In Vitro Investigation of Amyloid-<em>β</em> Hepatobiliary Disposition in Sandwich-Cultured Primary Rat Hepatocytes
AID  - 10.1124/dmd.113.052514
DP  - 2013 Oct 01
TA  - Drug Metabolism and Disposition
PG  - 1787--1796
VI  - 41
IP  - 10
4099  - http://dmd.aspetjournals.org/content/41/10/1787.short
4100  - http://dmd.aspetjournals.org/content/41/10/1787.full
SO  - Drug Metab Dispos2013 Oct 01; 41
AB  - Failure in amyloid-β (Aβ) systemic clearance across the liver has been suggested to play a role in Aβ brain accumulation and thus to contribute largely to the pathology of Alzheimer’s disease (AD). The purpose of this study was to characterize in vitro the transport mechanisms of Aβ40 across the liver using sandwich-cultured primary rat hepatocytes (SCHs) and to determine its biliary clearance (CLbile) and biliary excretion index (BEI%). 125I-Aβ40 BEI% was time dependent and reached steady state at 30 minutes, with an average value of 29.8% and a CLbile of 1.47 ml/min per kilogram of body weight. The role of low-density lipoprotein receptor–related protein-1 (LRP1) in mediating the basolateral uptake of 125I-Aβ40 in SCHs was assessed using receptor-associated protein (RAP, 2 µM). A significant reduction in 125I-Aβ40 BEI% and CLbile with RAP was observed, demonstrating a major contribution of LRP1 in mediating hepatic uptake of intact 125I-Aβ40 via transcytosis. Furthermore, activity studies suggested a lower role of receptor for advanced glycation end products (RAGE) in 125I-Aβ40 hepatic uptake. Verapamil (50 µM) and valspodar (20 µM) significantly reduced 125I-Aβ40 BEI%, indicating a role for P-glycoprotein (P-gp) in the biliary excretion of 125I-Aβ40 in SCHs. LRP1- and P-gp-mediated 125I-Aβ40 biliary excretion was inducible and increased BEI% by 26% after rifampicin pretreatment. In conclusion, our findings demonstrated that besides LRP1, P-gp and, to a lesser extent, RAGE are involved in 125I-Aβ40 hepatobiliary disposition and support the use of enhancement of Aβ hepatic clearance via LRP1 and P-gp induction as a novel therapeutic approach for the prevention and treatment of AD.