Fluconazole Penetration into Cerebrospinal Fluid in Humans

Foulds, George; Brennan, Doreen R.; Wajszczuk, Charles P.; Catanzaro, Antonino; Garg, Dyal C.; Knopf, William D.; Rinaldi, Michael G.; Weidler, Donald J.

doi:10.1002/j.1552-4604.1988.tb03159.x

Cited by 114 publications

(38 citation statements)

References 20 publications

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“…Data from human studies suggest that fluconazole concentrations in CSF are dose dependent and vary between 50% and 100% of the concentration observed in the plasma (67,68,69,70) ( Fig. 3 and 7).…”

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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Section: Brain and Cerebrospinal Fluidmentioning

confidence: 99%

Tissue Penetration of Antifungal Agents

Troke²,

2014

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“…The recommended dosage of p.o. fluconazole for the treatment of fungal infections in patients with AIDS is based upon pharmacokinetic data derived from healthy volunteers (4,14,21). The objective of this study was to determine the p.o.…”

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Pharmacokinetics and bioavailability of fluconazole in patients with AIDS

DeMuria

Forrest

Rich

et al. 1993

Antimicrob Agents Chemother

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Fluconazole pharmacokinetics were evaluated for 10 volunteers with AIDS who had no clinical evidence of gastroenteritis. Single 100-mg intravenous (i.v.) and oral (p.o.) doses were administered in a randomized, crossover design. i.v. doses were delivered by a constant-rate infusion over 30 min. Serum fluconazole concentrations were measured by gas-liquid chromatography. The i.v. and p.o. studies were modelled simultaneously by iterative two-stage analysis, which provided individual parameter estimates and a population pharmacokinetic model. Median areas under the concentration-time curves for i.v. and p.o. studies did not differ (90.6 and 99.3 ,ug/ml. h, respectively). Consistent with this finding, the median fractional bioavailability was 1.1 (range, 0.45 to 1.3), comparable to those in healthy subjects. Serum pharmacokinetics in these AIDS patients were generally similar to published data for healthy volunteers. However, foliowing p.o. dosing, we observed a slightly delayed and highly variable time to maximum concentration in serum (median, 2 h; range, 15 min to 8 h). Data were well described by a linear, two-compartment pharmacokinetic model with first-order absorption and elimination. Repeated-measures analysis ofvariance found no significant differences among any of the pharmacokinetic parameters between i.v. and p.o. studies. On the basis of our findings, we suggest no change in dosage of p.o. fluconazole in patients with AIDS who show no clinical signs of enteropathy.Oral (p.o.) fluconazole is frequently administered to persons with AIDS for the treatment of commonly occurring fungal infections, including oropharyngeal and esophageal candidiasis (31) and cryptococcal meningitis (32). Frequently, AIDS patients have hypochlorhydria (23) and other physiologic and anatomic disturbances of the alimentary tract (17,22,25), although gastroenteral symptoms may be absent. Potentially, these factors could interfere with the overall absorption of p.o. administered agents, alter drug transit time, and influence efficacy (11,29).To our knowledge, the absorption of p.o. fluconazole in patients with AIDS has not been investigated. The recommended dosage of p.o. fluconazole for the treatment of fungal infections in patients with AIDS is based upon pharmacokinetic data derived from healthy volunteers (4,14,21). The objective of this study was to determine the p.o. bioavailability and pharmacokinetics of fluconazole in patients with AIDS.(Results of this investigation were presented at the VIIIth International Conference on AIDS/IIIrd STD World Congress, Amsterdam, The Netherlands, July 1992.) MATERIALS AND METHODSPatients and selection criteria. The study population consisted of ambulatory patients who were served by the Brigham and Women's Hospital and the Harvard Community Health Plan (Boston, Mass.). The study protocol was approved by the institutional review boards for human investigation of both institutions. Written informed consent was obtained from each subject.Volunteers who had AIDS (5) were eligible for the stu...

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“…It has desirable pharmacologic properties, including a relatively long half-life, the ability to be administered either orally or parenterally, and good penetration into cerebrospinal fluid (CSF) (1,3,5). With respect to side effects, it is superior to imidazole antifungal drugs introduced earlier (8).…”

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Assay of fluconazole by high-performance liquid chromatography with a mixed-phase column

Wallace

Harris

Gallegos

et al. 1992

Antimicrob Agents Chemother

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A mixed-phase liquid chromatographic column was used to assay fluconazole in plasma, serum, and cerebrospinal fluid. The assay was linear from 0.2 to 20 tLg/ml, with an average coefficient of variation of less than 5%. The partitioning of the drug between serum and cerebrospinal fluid was determined for 34 patients.The method was demonstrated to be suitable for both pharmacokinetic studies and monitoring of patients receiving treatment with this antifungal agent.Fluconazole is part of a growing family of triazole antifungal drugs which exhibit a broad spectrum of activity. It has desirable pharmacologic properties, including a relatively long half-life, the ability to be administered either orally or parenterally, and good penetration into cerebrospinal fluid (CSF) (1,3,5). With respect to side effects, it is superior to imidazole antifungal drugs introduced earlier (8). It has already been approved by the U.S. Food and Drug Administration for the treatment of certain systemic fungal infections and is currently in clinical use in the United States and Europe as well as in clinical trials for other applications. A continuing increase in systemic fungal infections concomitant with growing immunosuppressed population established the relevance of fluconazole in the drug treatment arena. ' Several assays are currently in use for determining fluconazole concentrations in biologic specimens. Both gas-liquid chromatographic (2, 4) and high-performance liquid chromatographic (HPLC) (7) assays have been reported. Bioassay techniques are also available (6).The assay described in this report is an HPLC method that is done with a m-ixed-phase column and UV spectrophotometric detection. It has been developed for determining drug concentrations in serum, plasma, and cerebrospinal fluid (CSF).MATERIALS AND METHODS Instrumentation. A model 5020 (Varian Instruments, Walnut Creek, Calif.) liquid chromatograph with a variablewavelength UV detector (Varian UV-50 or equivalent) was used. A Varian mixed-phase PTHAA-5 liquid chromatographic column (15 cm long; 4-mm inner diameter) was used.Reagents. Fluconazole and internal standard UK-54,373 [2 -(2,4 -difluorophenyl) -1,3 -bis(lH -1,2,4 -triazol -1 -yl) -2-propanol; Fig. 1 Chromatographic conditions. The mobile phase was prepared by mixing acetonitrile with filtered 0.051 M monobasic phosphate buffer adjusted to pH of 3.0 at 15:85 (vol/vol). The flow rate was 0.9 ml/min. The UV detector was set at a wavelength of 210 nm. The HPLC apparatus was operated at room temperature (25 to 28°C).Standards and controls. Stock standards at concentrations of 1 and 100 ,ug/ml in methanol were prepared by placing appropriate amounts of fluconazole in polypropylene tubes with screw-cap tops and then adding 0.10 ml of methanol. Working serum standards with fluconazole concentrations of 0.0, 0.2, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 40.0, 50.0, and 100 ,ug/ml were prepared by placing various amounts of the two stock standard solutions in 15-ml glass tubes, taking the methanol to near dryness, an...

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Fluconazole Penetration into Cerebrospinal Fluid in Humans

Cited by 114 publications

References 20 publications

Tissue Penetration of Antifungal Agents

Tissue Penetration of Antifungal Agents

Pharmacokinetics and bioavailability of fluconazole in patients with AIDS

Assay of fluconazole by high-performance liquid chromatography with a mixed-phase column

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