Pharmacokinetics of 18F-labeled fluconazole in healthy human subjects by positron emission tomography

Fischman, Alan J.; Alpert, Nathaniel M.; Livni, Eli; Ray, Stephen J.; Sinclair, I; Callahan, Ronald J.; Correia, John A.; Webb, Douglas; Strausś, H. William; Rubin, Robert H.

doi:10.1128/aac.37.6.1270

Cited by 93 publications

(53 citation statements)

References 30 publications

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“…The second technique refers to positron emission tomographic scanning used by Fischman et al [81] 18 F-labeled fluconazole was given to healthy volunteers and determined in the heart by PET. Its level there was almost twofold higher than in blood, indicating fluconazole efficacy in treating fungal infection of the heart, but also, from a pharmacokinetic point of view, drug accumulation in cardiac tissue [81].…”

Section: Antifungal and Anticancer Drugsmentioning

confidence: 99%

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Tylutki

Polak

2015

Biopharm & Drug Disp

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ABSTRACT:Little is known about the uptake of drugs into the human heart, although it is of great importance nowadays, when science desires to predict tissue level behavior rather than to measure it. Although the drug concentration in cardiac tissue seems a better predictor for physiological and electrophysiological changes than its level in plasma, knowledge of this value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissues as being one of the input parameters in physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is on whether a drug penetrates into heart tissue at a therapeutic level; the provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocyte electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate the heart. Much data are derived from postmortem studies and they provide insight to the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart.

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Section: Antifungal and Anticancer Drugsmentioning

confidence: 99%

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Tylutki

Polak

2015

Biopharm & Drug Disp

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“…Fluconazole is also readily detectable in human brain parenchyma. Studies with 18 F-fluconazole in volunteers showed brain tissue concentrations that were similar to those in plasma, with some minor regional variation (71). However, in five surgical patients, fluconazole brain tissue/plasma concentration ratios of 0.7 to 2.4 were measured when the fluconazole plasma concentrations were at 90% of steady-state values (72).…”

Section: Brain and Cerebrospinal Fluidmentioning

confidence: 99%

Tissue Penetration of Antifungal Agents

Troke²,

2014

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SUMMARY Understanding the tissue penetration of systemically administered antifungal agents is critical for a proper appreciation of their antifungal efficacy in animals and humans. Both the time course of an antifungal drug and its absolute concentrations within tissues may differ significantly from those observed in the bloodstream. In addition, tissue concentrations must also be interpreted within the context of the pathogenesis of the various invasive fungal infections, which differ significantly. There are major technical obstacles to the estimation of concentrations of antifungal agents in various tissue subcompartments, yet these agents, even those within the same class, may exhibit markedly different tissue distributions. This review explores these issues and provides a summary of tissue concentrations of 11 currently licensed systemic antifungal agents. It also explores the therapeutic implications of their distribution at various sites of infection.

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“…Therefore, we presumed that dermatophytes might also be resistant to fluconazole and were interested in the resistance mechanism of fluconazole in dermatophytes. Fischman et al reported that levels of fluconazole Ͼ10 g/g of human tissue were needed to treat infection with Cryptococcus neoformans, Coccidioides immitis, and Histoplasma capsulatum (5). This observation prompted us to adjust the concentration of fluconazole in the medium to 20 g/ml for our experiments on the effect of fluconazole and/or proteasome inhibitor on fungal growth.…”

Section: Discussionmentioning

confidence: 99%

Expression of Ubiquitin Gene in Microsporum canis and Trichophyton mentagrophytes Cultured with Fluconazole

Kano

Okabayashi

Nakamura

et al. 2001

Antimicrob Agents Chemother

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The expression of the ubiquitin (Ub) gene in dermatophytes was examined for its relation to resistance against the antifungal drug fluconazole. The nucleotide sequences and the deduced amino acid sequences of the Ub gene in Microsporum canis were proven to be 99% similar to those of the Ub gene in Trichophyton mentagrophytes. Expression of mRNA of Ub in M. canis and T. mentagrophytes was enhanced when the fungi were cultured with fluconazole. The antifungal activity of fluconazole against these dermatophytes was increased in the presence of Ub proteasome inhibitor.Selective protein degradation in eukaryotic cells is mainly carried out by the ubiquitin (Ub) system (7,17,18). Ub is a highly conserved 76-residue protein which is distributed in eukaryotic cells and linked to a vast range of proteins (19). The Ub system plays important roles in many cellular functions, including cell cycle control, signal transduction, transcriptional regulation, the nuclear transport process, receptor control by endocytosis, etc. (4, 19).Several Ubs have been identified in fungi (11,15,16) and analyzed for their functions in cell biology. Saccharomyces cerevisiae Ub genes, named UBI1, UBI2, UBI3, and UBI4 (10) were expressed under stress conditions including heat stress and starvation (4, 12). Aspergillus nidulans Ubs were strongly expressed in the presence of antifungal drugs like amphotericin B and miconazole (10). Therefore, we hypothesized that Ubs in fungi might be related to resistance against antifungal drugs.Dermatophytoses are dermatophyte infections in keratinized tissues, i.e., epidermis, hair, and nails (9). In a previous study (8), the Ub gene of Trichophyton mentagrophytes, the anamorph of Arthroderma benhamiae, which frequently causes human and animal infections (1), was cloned. The Ub gene of this dermatophyte encoded two Ub repeats (8).Microsporum canis infection is most common in dogs and cats, and these animals can sometimes transmit the disease to humans (9). Accordingly, M. canis and T. mentagrophytes infections in humans and animals are most frequently treated with antifungal drugs.In the present study, we have taken a genetic approach to the two Ub repeats in M. canis and T. mentagrophytes in relation to a possible role in resistance against antifungal drugs. MATERIALS AND METHODS Strains.A standard strain of Arthroderma otae, (Ϫ) mating type, VUT-77055 (6), the teleomorph of M. canis, and a standard strain of Arthroderma benhamiae, (ϩ) mating type, VUT-77011 (RV 26678) (1), one of the teleomorphs of T. mentagrophytes, were used in this study. Preparation of cDNA.The mycelial samples were obtained by culturing the dermatophytes in Sabouraud's dextrose broth (9) at 27°C for 7 days. The mycelia were collected by centrifugation at 15,000 ϫ g for 5 min, and then they were homogenized in liquid nitrogen. Total RNAs were extracted from 500-g samples with RNeasy total RNA kit (QIAGEN, Valencia, Calif.). Reverse transcription (RT) of the poly(A)ϩ RNA was performed with an Omniscript reverse transcriptase kit (QIAGEN)....

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Pharmacokinetics of 18F-labeled fluconazole in healthy human subjects by positron emission tomography

Cited by 93 publications

References 30 publications

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Tissue Penetration of Antifungal Agents

Expression of Ubiquitin Gene in Microsporum canis and Trichophyton mentagrophytes Cultured with Fluconazole

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