TY - JOUR T1 - Itraconazole-induced cholestasis: involvement of the inhibition of bile canalicular phospholipid translocator MDR3/ABCB4 JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.110.067256 SP - mol.110.067256 AU - Takashi Yoshikado AU - Tappei Takada AU - Takehito Yamamoto AU - Hiroko Yamaji AU - Kousei Ito AU - Tomofumi Santa AU - Hiromitsu Yokota AU - Yutaka Yatomi AU - Haruhiko Yoshida AU - Jun Goto AU - Shoji Tsuji AU - Hiroshi Suzuki Y1 - 2010/01/01 UR - http://molpharm.aspetjournals.org/content/early/2010/11/05/mol.110.067256.abstract N2 - Biliary secretion of bile acids and phospholipids, both of which are essential components of biliary micelles, are mediated by the bile salt export pump (BSEP/ABCB11) and multidrug resistance 3 P-glycoprotein (MDR3/ABCB4), respectively, and their genetic dysfunction leads to the acquisition of severe cholestatic diseases. In the present study, we found two patients suffering from itraconazole (ITZ)-induced cholestatic liver injury with markedly high serum ITZ concentrations. To characterize the effect of ITZ on bile formation in vivo, biliary bile acids and phospholipids were analyzed in ITZ-treated rats and it was revealed that biliary phospholipids, rather than bile acids, were drastically reduced in the presence of clinically relevant concentrations of ITZ. Moreover, by using MDR3-expressing LLC-PK1 cells, we found that MDR3-mediated efflux of [14C]phosphatidylcholine was significantly reduced by ITZ. In contrast, BSEP-mediated transport of [3H]taurocholate was not significantly affected by ITZ, which is consistent with our in vivo observations. In conclusion, this study suggests the involvement of the inhibition of MDR3-mediated biliary phospholipids secretion in ITZ-induced cholestasis. Our approach may be useful for analyzing mechanisms of drug-induced cholestasis and evaluating the cholestatic potential of clinically-used drugs and drug candidates. ER -