PT - JOURNAL ARTICLE AU - Yoshikado, Takashi AU - Takada, Tappei AU - Yamamoto, Takehito AU - Yamaji, Hiroko AU - Ito, Kousei AU - Santa, Tomofumi AU - Yokota, Hiromitsu AU - Yatomi, Yutaka AU - Yoshida, Haruhiko AU - Goto, Jun AU - Tsuji, Shoji AU - Suzuki, Hiroshi TI - Itraconazole-Induced Cholestasis: Involvement of the Inhibition of Bile Canalicular Phospholipid Translocator MDR3/ABCB4 AID - 10.1124/mol.110.067256 DP - 2011 Feb 01 TA - Molecular Pharmacology PG - 241--250 VI - 79 IP - 2 4099 - http://molpharm.aspetjournals.org/content/79/2/241.short 4100 - http://molpharm.aspetjournals.org/content/79/2/241.full SO - Mol Pharmacol2011 Feb 01; 79 AB - 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 with 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.