Hepatotoxicity Related to Itraconazole : Report of Three Cases

Adriaenssens, Bert; Roskams, Tania; Steger, P.H.; Steenbergen, H.W. van

doi:10.1179/acb.2001.055

Cited by 36 publications

(20 citation statements)

References 16 publications

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“…In addition, the liver biopsy specimens from patients with ITZ-induced liver injury showed histological patterns of cholestasis (Adriaenssens et al, 2001). In the present study, in patients 1, 2, and 3, ALP, ␥-GTP, and total bilirubin were increased during ITZ-administration (Fig.…”

Section: Discussionsupporting

confidence: 58%

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: Discussionsupporting

confidence: 58%

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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“…An analysis of the Food and Drug Administration Adverse Event Reporting System database (http://www.fda.gov/ Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ AdverseDrugEffects/) revealed that antimycotics are involved in approximately 3% of all DILI cases (Raschi et al, 2014). Moreover, antifungal azoles have been associated with elevated levels of serum liver enzymes as well as liver injury occasionally leading to liver failure (Hann et al, 1993;Gearhart, 1994;Adriaenssens et al, 2001;Chang et al, 2007). Therefore, we MDR3 Inhibition by Antifungals first tested the interaction of five clinically used antifungal azoles with MDR3: fluconazole, itraconazole, ketoconazole, posaconazole, and voriconazole.…”

Section: Discussionmentioning

confidence: 99%

Role of Multidrug Resistance Protein 3 in Antifungal-Induced Cholestasis

et al. 2016

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Drug-induced liver injury is an important clinical entity resulting in a considerable number of hospitalizations. While drug-induced cholestasis due to the inhibition of the bile salt export pump (BSEP) is well investigated, only limited information on the interaction of drugs with multidrug resistance protein 3 (MDR3) exists and its role in the pathogenesis of drug-induced cholestasis is poorly understood. Therefore, we aimed to study the interaction of drugs with MDR3 and the effect of drugs on canalicular lipid secretion in a newly established polarized cell line system that serves as a model of canalicular lipid secretion. LLC-PK 1 cells were stably transfected with human Na 1 -taurocholate cotransporting polypeptide, BSEP, MDR3, and ABCG5/G8 and grown in the Transwell system. Apical phospholipid secretion and taurocholate transport were assayed to investigate the effect of selected drugs on MDR3-mediated phospholipid secretion as well as inhibition of BSEP. The established cell line displayed vectorial bile salt transport and specific phosphatidylcholine secretion into the apical compartment. The antifungal azoles, posaconazole, itraconazole, and ketoconazole, significantly inhibited MDR3-mediated phosphatidylcholine secretion. In contrast, amoxicillin clavulanate and troglitazone did not interfere with MDR3 activity. Drugs interfering with MDR3 activity did not display a parallel inhibition of BSEP. Our in vitro model for MDR3-mediated phospholipid secretion facilitates parallel screening for MDR3 and BSEP inhibitors. Our data demonstrate that the cholestatic potential of certain drugs may be aggravated by simultaneous inhibition of BSEP and MDR3.

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“…The efficacy of itraconazole prophylaxis has been demonstrated in other immunocompromised patient populations, and it has been demonstrated to be similar to fluconazole in reducing fungal colonization in liver-transplant patients (20 -23). With the current clinical experience indicating that itraconazole is well tolerated with rarely reported cases of hepatotoxicity, we proceeded to study its efficacy in the liver-transplant population (24).…”

Section: Safety Evaluationmentioning

confidence: 99%