PT  - JOURNAL ARTICLE
AU  - Eun Ju Jeong
AU  - Huimin Lin
AU  - Ming Hu
TI  - Disposition Mechanisms of Raloxifene in the Human Intestinal Caco-2 Model
AID  - 10.1124/jpet.103.063925
DP  - 2004 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 376--385
VI  - 310
IP  - 1
4099  - http://jpet.aspetjournals.org/content/310/1/376.short
4100  - http://jpet.aspetjournals.org/content/310/1/376.full
SO  - J Pharmacol Exp Ther2004 Jul 01; 310
AB  - The purpose of this study was to determine the mechanisms responsible for transport of raloxifene and its hydrophilic conjugates. Human intestinal Caco-2 cell culture model and Caco-2 cell lysate were used for the studies. The results indicated that absorptive permeability (PAB) of raloxifene was lower than its secretory permeability (PAB). As the concentration increased, the efflux ratio (PBA/PAB) decreased, but PBA increased. PAB was also increased in the presence of verapamil and cyclosporine A, two P-glycoprotein inhibitors. Raloxifene was extensively metabolized into sulfated and glucuronidated conjugates. The extent of metabolism or clearance was decreased as the concentration increased from 3.4 (96%) to 30 (22%) μM. Multidrug resistance-related protein inhibitors MK-571 (C26H26ClN2O3S2) and leukotriene C4 significantly de creased (maximal 80%) apical efflux of both conjugates. They also significantly decreased (maximal 85%) basolateral efflux of glucuronides but not sulfates. On the other hand, organic anion transporter (OAT) inhibitor estrone sulfate and estrone glucuronide significantly decreased (maximal 50%) the efflux of sulfate from both sides but had variable effects on glucuronide efflux. Inhibition of conjugate efflux with the OAT inhibitor estrone sulfate was concentration dependent, which resulted in increased transport of intact raloxifene (maximal 90%). This increase in raloxifene transport was also observed in the presence of another OAT inhibitor estrone glucuronide (70%). In conclusion, this is the first report that inhibition of an efflux transporter responsible for the transport of metabolites can result in increase in the transport of the intact compound. It also provides additional explanation why raloxifene has low bioavailability but a long half-life. The American Society for Pharmacology and Experimental Therapeutics