Time Course of Cyclosporin/Itraconazole Interaction

Trenk, Dietmar; Brett, W.; Jähnchen, E.; Birnbaum, D

doi:10.1016/s0140-6736(87)91232-3

Cited by 53 publications

(19 citation statements)

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“…Case reports or small series of patients have also demonstrated this interaction in renal, heart, and lung transplant recipients, with an associated deterioration in renal function induced by CsA (15,16,26). However, one study failed to observe itraconazole and CsA interaction in patients with bone marrow transplantation during an average time of 4.4 weeks in which both drugs were administered together (19).…”

Section: Discussionmentioning

confidence: 99%

“…Itraconazole has not been compared with amphotericin B against invasive pulmonary aspergillosis in randomized clinical trials, although results of initial nonran-domized studies appear promising (6,7,30). However, among the concerns with antifungal azole derivatives, such as itraconazole, is their potential adverse interaction with CsA that may increase CsA levels, resulting also in nephrotoxicity (15,16,26), and their limited bioavailability in some patients that may lower concentrations in serum (6,25,27).…”

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confidence: 99%

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Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma

Berenguer

Ali

Allende

et al. 1994

Antimicrob Agents Chemother

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Itraconazole and amphotericin B were compared by using a newly developed model of invasive pulmonary aspergillosis in rabbits immunosuppressed with methylprednisolone and cyclosporin A (CsA). Both itraconazole at 40 mg/kg (given orally) and amphotericin B at 1 mg/kg (given intravenously) had in vivo antifungal activity in comparison with controls. At these dosages, amphotericin B was more effective than itraconazole in reducing the tissue burden (loglo CFU per gram) of Aspergillus fumigatus (P < 0.05) and the number of pulmonary lesions (P < 0.01). However, there was considerable variation in the near-peak concentrations of itraconazole in plasma (median, 4.15 ,ug/ml; range, <0.5 to 16.8 ,g/ml) and a strong inverse correlation between concentrations of itraconazole in plasma and the tissue burden ofA.fumigatus. An inhibitory sigmoid maximum-effect model predicted a significant pharmacodynamic relationship (r = 0.87, P < 0.001) between itraconazole concentrations in plasma and antifungal activity as a function of the tissue burden ofA.fumigatus.This model demonstrated that levels in plasma of greater than 6 ,ug/ml were associated with a significantly greater antifungal effect. Levels in plasma of less than 6 ,g/ml were associated with a rapid decline in the antifungal effect. Itraconazole, in comparison with amphotericin B, caused a twofold elevation of CsA levels (P < 0.01) but was less nephrotoxic (P < 0.01). This study of experimental pulmonary aspergillosis demonstrated that amphotericin B at 1 mg/kg/day was more active but more nephrotoxic than itraconazole at 40 mg/kg/day, that itraconazole increased concentrations of CsA in plasma, and that the antifungal activity of itraconazole strongly correlated with concentrations in plasma in an inhibitory sigmoid maximum-effect model. These findings further indicate the importance of monitoring concentrations of itraconazole in plasma as a guide to increasing dosage, improving bioavailability, and optimizing antifungal efficacy in the treatment of invasive pulmonary aspergillosis.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma

Berenguer

Ali

Allende

et al. 1994

Antimicrob Agents Chemother

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“…Drugs whose pharmacokinetics is significantly affected by ITZ include cyclosporine (Kwan et al, 1987;Trenk et al, 1987;Florea et al, 2003), tacrolimus (Banerjee et al, 2001;Mahnke et al, 2003), midazolam (Olkkola et al, 1996;Backman et al, 1998), buspirone (Kivistö et al, 1999), methylprednisolone (Lebrun-Vignes et al, 2001), lovastatin (Neuvonen and Jalava, 1996), and simvastatin . The observed increase in the in vivo AUC of these drugs is between 2-and 30-fold after concomitant administration of ITZ.…”

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confidence: 99%

Role of Itraconazole Metabolites in Cyp3a4 Inhibition

et al. 2004

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ABSTRACT:Itraconazole (ITZ) is a potent inhibitor of CYP3A in vivo. However, unbound plasma concentrations of ITZ are much lower than its reported in vitro K i , and no clinically significant interactions would be expected based on a reversible mechanism of inhibition. The purpose of this study was to evaluate the reasons for the in vitro-in vivo discrepancy. The metabolism of ITZ by CYP3A4 was studied.

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“…Sterol biosynthesis inhibition at the stage ofC-14 demethylation is the primary mode of action (8). Recently, a synergism between triazole agents ketaconazol, itraconazole, and cyclosporin A (CsA) has been reported (10,14). We have shown earlier that CsA reverses multidrug resistance in tumor cells both in vitro and in vivo (5,6).…”

Section: Discussionmentioning

confidence: 99%

“…Recently we have shown that cyclosporin A, a lipophilic agent that partitions between plasma membranes, reverses multidrug resistance both in vitro and in vivo (5,6). Itraconazole, a new generation 1,2,4 triazole antifungal agent that inhibits different cytochrome P-450 systems (7)(8)(9), has been shown to synergize with cyclosporin A (10). Therefore, we set out to explore the possibility of whether similar synergism would exist between these two compounds in reversing MDR in vitro.…”

Section: Introductionmentioning

confidence: 99%

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

Gupta

Kim²,

Gollapudi³

1991

J. Clin. Invest.

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Itraconazole is a recently developed triazole antifungal agent that inhibits cell membrane sterol biosynthesis. Itraconazole, in a dose-dependent manner, enhanced intracellular accumulation of daunorubicin and reversed the drug resistance in murine leukemia P388/ADR cells. In addition, itraconazole corrected the altered plasma membrane potentials of P388/ADR cells. The concentrations of itraconazole that reversed drug resistance are comparable to the plasma levels achieved by therapeutic dosage used in the treatment of fungal infections. Therefore, itraconazole is a potential candidate for in vivo use to reverse multidrug resistance in cancer with added benefit of its antifungal property. (J. Clin.

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Time Course of Cyclosporin/Itraconazole Interaction

Cited by 53 publications

References 0 publications

Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma

Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma

Role of Itraconazole Metabolites in Cyp3a4 Inhibition

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

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