Role of Itraconazole Metabolites in Cyp3a4 Inhibition

Isoherranen, Nina; Kunze, Kent L.; Allen, Kyle E.; Nelson, Wendel L.; Thummel, Kenneth E.

doi:10.1124/dmd.104.000315

Cited by 239 publications

(235 citation statements)

References 33 publications

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“…This may explain the potency of CYP3A4 inhibition seen with itraconazole. 59 Recently, itraconazole was shown to be a substrate for the phase II enzyme UGT1A4, with an affinity similar to that of the imidazole antifungal agents, and it may also be an inhibitor of UGT1A4. 49 Itraconazole interacts with several genetically variable drug transporters and CYP enzymes, thus implicating them in the observed variability of itraconazole levels.…”

Section: Triazole Antifungalsmentioning

confidence: 99%

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Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Ashbee

Gilleece

2011

Bone Marrow Transplant

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Section: Triazole Antifungalsmentioning

confidence: 99%

“…58 More than 30 metabolites are formed, 57 including hydroxy-itraconazole, 59,60 all of which are inhibitors of CYP3A4 and have a higher affinity for CYP3A4 than itraconazole itself. This may explain the potency of CYP3A4 inhibition seen with itraconazole.…”

Section: Triazole Antifungalsmentioning

confidence: 99%

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Ashbee

Gilleece

2011

Bone Marrow Transplant

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“…The slowly dissociating inhibitory mode is, however, not a necessary condition for burst kinetics. Interestingly, although the steady state rate of ITZ-OH formation may be complicated by further metabolism of the product ITZ-OH, the available published data do suggest 'burst' kinetics for the commercial mixture of ITZ diastereomers [27]. No published studies have examined the kinetic behavior of KTZ as a substrate.…”

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confidence: 99%

Surface Plasmon Resonance Analysis of Antifungal Azoles Binding to CYP3A4 with Kinetic Resolution of Multiple Binding Orientations

et al. 2006

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The heme-containing Cytochrome P450s (CYPs) are a major enzymatic determinant of drug clearance and drug-drug interactions. The CYP3A4 isoform is inhibited by antifungal imidazoles or triazoles, which form low spin heme iron complexes via formation of a nitrogen-ferric iron coordinate bond. However, CYP3A4 also slowly oxidizes the antifungal itraconazole (ITZ) at a site that is ∼ 25 Å from the triazole nitrogens, suggesting that large antifungal azoles can adopt multiple orientations within the CYP3A4 active site. Here, we report a surface plasmon resonance (SPR) analysis with kinetic resolution of two binding modes of ITZ, and the related drug ketoconazole (KTZ). SPR reveals a very slow off-rate for one binding orientation. Multiphasic binding kinetics are observed and one of the two binding components resolved by curve-fitting exhibits 'equilibrium overshoot'. Pre-loading of CYP3A4 with the heme ligand imidazole abolishes this component of the antifungal azole binding trajectories, and it eliminates the conspicuously slow off-rate. The fractional populations of CYP3A4 complexes corresponding to different drug orientations can be manipulated by altering the duration of the pulse of drug exposure. UV-vis difference absorbance titrations yield low spin spectra and K D values that are consistent with the high affinity complex resolved by SPR. These results demonstrate that ITZ and KTZ bind in multiple orientations, including a catalytically productive mode and a slowly-dissociating inhibitory mode. Most importantly, they provide the first example of an SPR-based method for the kinetic characterization of drug binding to any human CYP, including mechanistic insight not available from other methods. Keywords protein-ligand interactions; tight binding inhibitors; drug metabolism; drug interactionsThe hepatic and intestinal heme-containing Cytochrome P450s (CYPs) 1 oxidize most drugs, and thus play a critical role in their metabolism and disposition [1][2][3]. Among the various human CYP isoforms, CYP3A4 contributes most to drug metabolism. CYP3A4 exhibits complex allosteric kinetics, which may result from drug-drug interactions on a single CYP molecule through multiple drug binding, as suggested by steady state kinetic behavior [4][5][6], large active sites observed in crystal structures [7][8][9][10] and spectroscopic studies [11]. Complex kinetics † This work was supported by NIH grants GM32165 (WMA, NI, KLK) and GM07750 (JTP). * Corresponding author: Tel: (206) FAX: (206) [12][13][14][15], and equilibrium optical titrations that rely on the inhibitor-or substrate-dependent changes in ferric spin state equilibrium [16][17][18]. The complexity of CYP kinetics severely impedes prediction of drug clearance and drug-drug interactions [12][13][14][15]19]. Clearly, new methods are required to elucidate the molecular basis of CYP allosterism and complex inhibitor or substrate binding.The antifungal azoles, including ketoconazole (KTZ) and itraconazole (ITZ), historically have been considered to be potent inh...

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“…Therefore, the second and third metabolites were included, resulting in a model that slightly overpredicts the first dose of some studies, but accurately describes the steady‐state plasma concentrations of intravenous and oral multiple‐dose administration. The CYP3A4 inhibition constants of itraconazole and all three metabolites were fixed to literature values 18. Furthermore, the model correctly describes the strong food effects for both oral solution and capsule formulation, which is essential for modeling of the reported clinical studies.…”

Section: Discussionmentioning

confidence: 99%

PBPK Models for CYP3A4 and P‐gp DDI Prediction: A Modeling Network of Rifampicin, Itraconazole, Clarithromycin, Midazolam, Alfentanil, and Digoxin

Hanke

Frechen

Moj

et al. 2018

CPT Pharmacom & Syst Pharma

129

137

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According to current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidance documents, physiologically based pharmacokinetic (PBPK) modeling is a powerful tool to explore and quantitatively predict drug‐drug interactions (DDIs) and may offer an alternative to dedicated clinical trials. This study provides whole‐body PBPK models of rifampicin, itraconazole, clarithromycin, midazolam, alfentanil, and digoxin within the Open Systems Pharmacology (OSP) Suite. All models were built independently, coupled using reported interaction parameters, and mutually evaluated to verify their predictive performance by simulating published clinical DDI studies. In total, 112 studies were used for model development and 57 studies for DDI prediction. 93% of the predicted area under the plasma concentration‐time curve (AUC) ratios and 94% of the peak plasma concentration (Cmax) ratios are within twofold of the observed values. This study lays a cornerstone for the qualification of the OSP platform with regard to reliable PBPK predictions of enzyme‐mediated and transporter‐mediated DDIs during model‐informed drug development. All presented models are provided open‐source and transparently documented.

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Role of Itraconazole Metabolites in Cyp3a4 Inhibition

Cited by 239 publications

References 33 publications

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Surface Plasmon Resonance Analysis of Antifungal Azoles Binding to CYP3A4 with Kinetic Resolution of Multiple Binding Orientations

PBPK Models for CYP3A4 and P‐gp DDI Prediction: A Modeling Network of Rifampicin, Itraconazole, Clarithromycin, Midazolam, Alfentanil, and Digoxin

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