Considerations for Using Ketoconazole in Solid Organ Transplant Recipients Receiving Cyclosporine Immunosuppression

Chapman, Scott A; Lake, Kathleen D.; Solbrack, Diane F; Milfred, Sherry K.; Marshall, Peter S.; Kamps, Melissa

doi:10.1177/090591999600600310

Cited by 3 publications

(3 citation statements)

References 59 publications

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“…The daily dosage is 200–400 mg. Ketoconazole displays a broad spectrum of antifungal activity, good oral bioavailability, and is in general well tolerated. Moreover, over the years of use it was reported to be beneficial in anticancer chemotherapy (Trachtenberg et al 1983; Trachtenberg and Pont, 1984; Lopez-Barcons et al 2017) or therapy of organ transplant recipients receiving cyclosporine immunosuppression (Chapman et al 1996; Carbajal et al 2004). The downside of ketoconazole is a short lifetime in human blood because the drug is rapidly metabolized in the liver (Dalvie et al 2002), where it interacts with many drug-metabolizing cytochromes P450, CYP3A4 in particular (Mosca et al 1985; Zhang et al 2002).…”

Section: Clinical Azole Antifungals Of Systemic Usementioning

confidence: 99%

CYP51 as drug targets for fungi and protozoan parasites: past, present and future

2018

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The efficiency of treatment of human infections with the unicellular eukaryotic pathogens such as fungi and protozoa remains deeply unsatisfactory. For example, the mortality rates from nosocomial fungemia in critically ill, immunosuppressed or post-cancer patients often exceed 50%. A set of six systemic clinical azoles [sterol 14α-demethylase (CYP51) inhibitors] represents the first-line antifungal treatment. All these drugs were discovered empirically, by monitoring their effects on fungal cell growth, though it had been proven that they kill fungal cells by blocking the biosynthesis of ergosterol in fungi at the stage of 14α-demethylation of the sterol nucleus. This review briefs the history of antifungal azoles, outlines the situation with the current clinical azole-based drugs, describes the attempts of their repurposing for treatment of human infections with the protozoan parasites that, similar to fungi, also produce endogenous sterols, and discusses the most recently acquired knowledge on the CYP51 structure/function and inhibition. It is our belief that this information should be helpful in shifting from the traditional phenotypic screening to the actual target-driven drug discovery paradigm, which will rationalize and substantially accelerate the development of new, more efficient and pathogen-oriented CYP51 inhibitors.

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Section: Clinical Azole Antifungals Of Systemic Usementioning

confidence: 99%

CYP51 as drug targets for fungi and protozoan parasites: past, present and future

2018

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“…Unintentional inhibition of CYP3A4 can lead to increased bioavailability of the competing drug substrate and result in toxicity. , On the other hand, drug–drug interactions can be beneficial in some scenarios. An increase in drug bioavailability due to CYP3A4 inhibition can lead to productive, cost-effective treatments. , Additionally, CYP genes vary among ethnic groups causing inconsistency in pharmacokinetic responses among people . Induction is another challenge associated with CYPs.…”

Section: Introductionmentioning

confidence: 99%

Dynamic Ir(III) Photosensors for the Major Human Drug-Metabolizing Enzyme Cytochrome P450 3A4

et al. 2023

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Probing the activity of cytochrome P450 3A4 (CYP3A4) is critical for monitoring the metabolism of pharmaceuticals and identifying drug–drug interactions. A library of Ir(III) probes that detect occupancy of the CYP3A4 active site were synthesized and characterized. These probes show selectivity for CYP3A4 inhibition, low cellular toxicity, K d values as low as 9 nM, and are highly emissive with lifetimes up to 3.8 μs in cell growth media under aerobic conditions. These long emission lifetimes allow for time-resolved gating to distinguish probe from background autofluorescence from growth media and live cells. X-ray crystallographic analysis revealed structure–activity relationships and the preference or indifference of CYP3A4 toward resolved stereoisomers. Ir(III)-based probes show emission quenching upon CYP3A4 binding, then emission increases following displacement with CYP3A4 inhibitors or substrates. Importantly, the lead probes inhibit the activity of CYP3A4 at concentrations as low as 300 nM in CYP3A4-overexpressing HepG2 cells that accurately mimic human hepatic drug metabolism. Thus, the Ir(III)-based agents show promise as novel chemical tools for monitoring CYP3A4 active site occupancy in a high-throughput manner to gain insight into drug metabolism and drug–drug interactions.

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“…One way to overcome fast drug metabolism is the inhibition of CYP3A4. Currently, two CYP3A4 inhibitors, ritonavir and cobicistat, are part of multidrug therapies for treating HIV and hepatitis C virus (HCV) infections, whereas ketoconazole is co-prescribed with the quickly metabolized immunosuppressants in organ transplant patients. − Anticancer therapy is another field where targeted CYP3A4 inhibition holds promise. CYP3A4 clears various types of anticancer drugs via both intestinal/hepatic metabolism and enhanced expression/ in situ metabolism in solid tumors. − Targeted inhibition of CYP3A4 in tumors has been identified as a potential solution to improve efficacy of chemotherapy by restoring sensitivity of cancer cells. , Since most anticancer drugs have a narrow therapeutic index, potent CYP3A4 inhibition (as part of drug cocktails) has great potential to improve outcomes, lower chemotherapeutic doses, and minimize adverse effects.…”

Section: Introductionmentioning

confidence: 99%

Photosensitive Ru(II) Complexes as Inhibitors of the Major Human Drug Metabolizing Enzyme CYP3A4

et al. 2021

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We report the synthesis and photochemical and biological characterization of the first selective and potent metal-based inhibitors of cytochrome P450 3A4 (CYP3A4), the major human drug metabolizing enzyme. Five Ru(II)-based derivatives were prepared from two analogs of the CYP3A4 inhibitor ritonavir, 4 and 6: [Ru(tpy)(L)(6)]Cl2 (tpy = 2,2′:6′,2″-terpyridine) with L = 6,6′-dimethyl-2,2′-bipyridine (Me2bpy; 8), dimethylbenzo[i]dipyrido[3,2-a:2′,3′-c]phenazine (Me2dppn; 10) and 3,6-dimethyl-10,15-diphenylbenzo[i]dipyrido[3,2-a:2′,3′-c]phenazine (Me2Ph2dppn; 11), [Ru(tpy)(Me2bpy)(4)]Cl2 (7) and [Ru(tpy)(Me2dppn)(4)]Cl2 (9). Photochemical release of 4 or 6 from 7–11 was demonstrated, and the spectrophotometric evaluation of 7 showed that it behaves similarly to free 4 (type II heme ligation) after irradiation with visible light but not in the dark. Unexpectedly, the intact Ru(II) complexes 7 and 8 were found to inhibit CYP3A4 potently and specifically through direct binding to the active site without heme ligation. Caged inhibitors 9–11 showed dual action properties by combining photoactivated dissociation of 4 or 6 with efficient 1O2 production. In prostate adenocarcinoma DU-145 cells, compound 9 had the best synergistic effect with vinblastine, the anticancer drug primarily metabolized by CYP3A4 in vivo. Thus, our study establishes a new paradigm in CYP inhibition using metalated complexes and suggests possible utilization of photoactive CYP3A4 inhibitory compounds in clinical applications, such as enhancement of therapeutic efficacy of anticancer drugs.

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Considerations for Using Ketoconazole in Solid Organ Transplant Recipients Receiving Cyclosporine Immunosuppression

Cited by 3 publications

References 59 publications

CYP51 as drug targets for fungi and protozoan parasites: past, present and future

CYP51 as drug targets for fungi and protozoan parasites: past, present and future

Dynamic Ir(III) Photosensors for the Major Human Drug-Metabolizing Enzyme Cytochrome P450 3A4

Photosensitive Ru(II) Complexes as Inhibitors of the Major Human Drug Metabolizing Enzyme CYP3A4

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