Reversal of daunorubicin resistance in P388/ADR cells by itraconazole.

Gupta, Sudhir; Kim, J; Gollapudi, Sastry

doi:10.1172/jci115154

Cited by 51 publications

(31 citation statements)

References 18 publications

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“…Because MDR3/ABCB4 has the closest similarity to MDR1/ABCB1 among genes in the ABC transporter family and is known to have some overlapping substrate specificities with MDR1, such as digoxin, paclitaxel, and vinblastine (Smith et al, 2000), cholestatic drugs that can act as MDR1 inhibitors may also inhibit MDR3-mediated biliary secretion of phospholipids. In fact, ITZ is a potential inhibitor of MDR1 (Gupta et al, 1991;Takara et al, 1999;Iida et al, 2001) and MDR3. Furthermore, tacrine, which often increases LFTs, may also have an inhibitory effect on MDR3; its risk of hepatotoxicity was particularly high in humans carrying some variants of the MDR3 gene (Alfirevic et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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

Yoshikado

Takada

Yamamoto³

et al. 2010

Mol Pharmacol

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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.

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Section: Discussionmentioning

confidence: 99%

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

Yoshikado

Takada

Yamamoto³

et al. 2010

Mol Pharmacol

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“…Itraconazole can also reverse resistance to the P-gp substrate daunorubicin (DNR) in a murine acute leukemia cell line in vitro (multidrug-resistant cells) (13), while the methylthiazolyl diphenyltetrazolium bromide (MTT) cytotoxicity assay results suggest an interaction of itraconazole with MDR and/or multidrug resistance protein (MRP)-associated resistance because of resistance reversal (18). The transport of vinblastine, DNR, and doxorubicin is affected by 100 M itraconazole in cells transfected with MDR1 cDNA (31).…”

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confidence: 99%

“…The transport of vinblastine, DNR, and doxorubicin is affected by 100 M itraconazole in cells transfected with MDR1 cDNA (31). Furthermore, clinical interactions have been reported following coadministration of itraconazole with vincristine (2), DNR (13,33), quinidine (16), or digoxin (15), all of which, it has been asserted, are P-gp substrates (with the first three being well characterized). Lovastatin concentrations increased more than 20-fold when it was coadministered with itraconazole (22).…”

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confidence: 99%

Interaction of Common Azole Antifungals with P Glycoprotein

Wang¹,

Lew²,

Casciano³

et al. 2002

Antimicrob Agents Chemother

213

151

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Both eucaryotic and procaryotic cells are resistant to a large number of antibiotics because of the activities of export transporters. The most studied transporter in the mammalian ATP-binding cassette transporter superfamily, P glycoprotein (P-gp), ejects many structurally unrelated amphiphilic and lipophilic xenobiotics. Observed clinical interactions and some in vitro studies suggest that azole antifungals may interact with P-gp. Such an interaction could both affect the disposition and exposure to azole antifungal therapeutics and partially explain the clinical drug interactions observed with some antifungals. Using a whole-cell assay in which the retention of a marker substrate is evaluated and quantified, we studied the abilities of the most widely prescribed orally administered azole antifungals to inhibit the function of this transporter. In a cell line presenting an overexpressed amount of the human P-gp transporter, itraconazole and ketoconazole inhibited P-gp function with 50% inhibitory concentrations (IC 50 s) of ϳ2 and ϳ6 M, respectively. Cyclosporin A was inhibitory with an IC 50 of 1.4 M in this system. Uniquely, fluconazole had no effect in this assay, a result consistent with known clinical interactions. The effects of these azole antifungals on ATP consumption by P-gp (representing transport activity) were also assessed, and the K m values were congruent with the IC 50 s. Therefore, exposure of tissue to the azole antifungals may be modulated by human P-gp, and the clinical interactions of azole antifungals with other drugs may be due, in part, to inhibition of P-gp transport.

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“…22) Reversal of resistance has also been reported for itraconazole, where daunorubicin and adriamycin resistance was reversed at a concentration of 1-2.5 mg/ml in P388/ADR 23) and K562/ADR, 24) respectively. The data on the interactions of antifungal drugs with MDR1 varied depending on the experimental system, and no a) The values are the meansϮS.D.…”

Section: )mentioning

confidence: 73%