Effect of the CYP3A inhibitor ketoconazole on the PXR-mediated induction of CYP3A activity

Fuchs, Ines; Hafner-Blumenstiel, Verena; Markert, Christoph; Burhenne, Jürgen; Weiß, Johanna; Haefeli, Walter E.; Mikus, Gerd

doi:10.1007/s00228-012-1388-1

Cited by 32 publications

(24 citation statements)

References 26 publications

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“…The partial metabolic clearance to norfentanyl was largely reduced to 18% during administration of ketoconazole, which clearly demonstrates for the first time in vivo the strong inhibition of the N-dealkylation pathway by ketoconazole. This effect is comparable to midazolam inhibition by ketoconazole where a single oral dose of 400 milligrams reduced midazolam partial metabolic clearances by 82% 29 and multiple doses of ketoconazole (400 milligrams once daily) reduced the apparent oral clearance of midazolam by 92.8%. 30 This is explained by formation of 1 0 -hydroxymidazolam from midazolam being almost exclusively catalyzed by CYP3A.…”

Section: Fentanyl Metabolic Clearancesmentioning

confidence: 74%

Pharmacokinetic interaction of intravenous fentanyl with ketoconazole

Ziesenitz

König

Mahlke

et al. 2015

The Journal of Clinical Pharmacology

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Fentanyl is primarily metabolized by CYP3A, but has also been suggested to act as a weak inhibitor of CYP3A. We investigated the influence of CYP3A inhibition by ketoconazole on the pharmacokinetics of intravenously administered fentanyl and the effect of fentanyl on CYP3A activity. A prospective, open-label, randomized, monocentre, crossover study was conducted in 16 healthy volunteers. They received fentanyl alone (5 microgram per kilogram) or fentanyl plus ketoconazole (200 milligram orally B.I.D. over 2 days). Naloxone (2 × 0.2 milligram i.v.) was given simultaneously with fentanyl to mitigate any opioid effect. Midazolam was administered as a CYP3A probe drug. Fentanyl and its metabolites were quantified by LC/MS/MS in blood and urine samples obtained over 24 hour. Exposure of fentanyl (AUC0- ∞ ) was significantly increased to 133% and systemic clearance was reduced to 78% by ketoconazole, norfentanyl formation was significantly delayed and partial metabolic clearance decreased to 18%. Fentanyl had no influence on midazolam exposure and CYP3A activity whereas ketoconazole decreased CYP3A activity to 13%. Although fentanyl N-dealkylation is substantially inhibited by ketoconazole, exposure of fentanyl itself increased by one third only. Clinically fentanyl dosage adjustments may become necessary when ketoconazole or other strong CYP3A inhibitors are given simultaneously. Fentanyl itself does not influence CYP3A activity.

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Section: Fentanyl Metabolic Clearancesmentioning

confidence: 74%

Pharmacokinetic interaction of intravenous fentanyl with ketoconazole

Ziesenitz

König

Mahlke

et al. 2015

The Journal of Clinical Pharmacology

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“…The partial metabolic clearance of midazolam to its metabolite 1′‐hydroxy‐midazolam (1′‐OH‐midazolam) can be calculated from the plasma exposure data and serves as a measure of the CYP3A activity . This method has already been used to obtain information on the CYP3A activity in healthy volunteers as well as in patients …”

Section: Introductionmentioning

confidence: 99%

“…4,5 This method has already been used to obtain information on the CYP3A activity in healthy volunteers as well as in patients. 3,6,7 The aim of the present study was to address the variability of CYP3A activity, which is critical for the elimination of a large number of drugs thereby improving pharmacological symptom management and supportive therapies in palliative patients with haematological diseases. clinical study was taken out at the Department of Hematology, Oncology and Rheumatology of Heidelberg University Hospital.…”

Section: Introductionmentioning

confidence: 99%

Decreased Cytochrome P450 3A activity in palliative patients with haematological diseases: Potential impact on supportive drug therapies

Geist

Siller

Egerer

et al. 2019

Basic Clin Pharma Tox

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Cytochrome P450 3A (CYP3A) is the most relevant drug‐metabolizing enzyme in human beings involved in the elimination of about 50% of the marketed drugs. Comprehensive in vivo data of CYP3A activity in palliative patients with haematological diseases are missing. Therefore, CYP3A activity was determined under real‐life clinical conditions in patients to gain knowledge about dose adjustments for supportive therapies and symptom management in haematology. The single‐arm, prospective trial obtained a 4‐hours pharmacokinetic profile of midazolam after oral administration of a microdose as marker substance from each enrolled patient. Plasma concentrations of midazolam and its primary metabolite 1′‐hydroxy‐midazolam were quantified by mass spectrometry techniques. CYP3A activity was calculated as partial metabolic clearance from an established limited sampling area under the curve. All other drugs taken by the participating patients were considered as well as recent laboratory test results and the patients' diagnoses. Partial metabolic clearance of midazolam in patients with haematological diseases was highly variable (36.9 ± 52.7 L/h). In comparison with the CYP3A activity of healthy individuals, this was a highly significant 30% reduction of activity (P < 0.0001). Dosing of major CYP3A substrate drugs needs to be reduced in palliative patients with haematological diseases, otherwise escalation of debilitating symptoms due to drug interactions might occur.

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“…Notably, because these are diverse chemical entities, it is quite clear that many of the compounds bind other targets at concentrations well below the range that affects PXR (e.g., ketoconazole) (Ekins et al, 2007). Indeed, this is borne out by the fact that concentrations of ketoconazole used for therapeutic purposes are clearly not high enough or sustained (>10 μM for at least 48–72 hours) to antagonize PXR activation in vivo (Fuchs et al, 2012), and thus would lead to the erroneous conclusion that ketoconazole would not inhibit PXR activation in vivo . The doses required to inhibit PXR in vivo would likely to yield unacceptable toxicity, and these issues have led toward a search for safer and more high-potency ketoconazole analogs that antagonize PXR (Dvorak, 2011; Das et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

PXR antagonists and implication in drug metabolism

Mani

Dou

Redinbo

2013

Drug Metabolism Reviews

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Adopted orphan nuclear receptor (NR), pregnane X receptor (PXR), plays a central role in the regulation of xeno- and endobiotic metabolism. Since the discovery of the functional role of PXR in 1998, there is evolving evidence for the role of PXR agonists in abrogating metabolic pathophysiology (e.g., cholestasis, hypercholesterolemia, and inflammation). However, more recently, it is clear that PXR is also an important mediator of adverse xeno- (e.g., enhances acetaminophen toxicity) and endobiotic (e.g., hepatic steatosis) metabolic phenotypes. Moreover, in cancer therapeutics, PXR activation can induce drug resistance, and there is growing evidence for tissue-specific enhancement of the malignant phenotype. Thus, in these instances, there may be a role for PXR antagonists. However, as opposed to the discovery efforts for PXR agonists, there are only a few antagonists described. The mode of action of these antagonists (e.g., sulforaphane) remains less clear. Our laboratory efforts have focused on this question. Since the original discovery of azoles analogs as PXR antagonists, we have preliminarily defined an important PXR antagonist pharmacophore and developed less-toxic PXR antagonists. In this review, we describe our published and unpublished findings on recent structure-function studies involving the azole chemical scaffold. Further work in the future is needed to fully define potent, more-selective PXR antagonists that may be useful in clinical application.

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Effect of the CYP3A inhibitor ketoconazole on the PXR-mediated induction of CYP3A activity

Abstract: Ketoconazole is a strong inhibitor of CYP3A, also when used concomitantly with St John's wort. In therapeutic doses it does not inhibit pregnane X receptor-mediated induction of CYP3A in vivo.

Cited by 32 publications

References 26 publications

Pharmacokinetic interaction of intravenous fentanyl with ketoconazole

Pharmacokinetic interaction of intravenous fentanyl with ketoconazole

Decreased Cytochrome P450 3A activity in palliative patients with haematological diseases: Potential impact on supportive drug therapies

PXR antagonists and implication in drug metabolism

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