Itraconazole-Induced Cholestasis: Involvement of the Inhibition of Bile Canalicular Phospholipid Translocator MDR3/ABCB4

作者：Yoshikado Takashi; Takada Tappei^*; Yamamoto Takehito; Yamaji Hiroko; Ito Kousei; Santa Tomofumi; Yokota Hiromitsu; Yatomi Yutaka; Yoshida Haruhiko; Goto Jun; Tsuji Shoji; Suzuki Hiroshi

来源：Molecular Pharmacology, 2011, 79(2): 241-250.

DOI：10.1124/mol.110.067256

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 [(14)C] phosphatidylcholine was significantly reduced by ITZ. In contrast, BSEP-mediated transport of [(3)H] 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.

• 出版日期2011-2