Bioassay for serum itraconazole concentrations using hydroxyitraconazole standards

Law, Derek; Moore, Caroline B.; Denning, David W.

doi:10.1128/aac.38.7.1561

Cited by 54 publications

(41 citation statements)

References 13 publications

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“…It has previously been reported that there were similar discrepancies in bioassay and HPLC-based determinations in humans (13,30). We confirmed from the following evidence that itraconazole was converted into an active metabolite in mice.…”

Section: Discussionsupporting

confidence: 77%

“…The conversion of itraconazole to an active metabolite, hydroxy-itraconazole, has also been confirmed in humans (8,9). The antifungal titer obtained in our results suggested that the pharmacodynamic activity of the metabolite was comparable to that of itraconazole in mice as well as humans (4,13,23,31). The parent compound and its active metabolite would shared in vivo activities against C. albicans and A. fumigatus in mice.…”

Section: Discussionsupporting

confidence: 57%

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Determination of Antifungal Activities in Serum Samples from Mice Treated with Different Antifungal Drugs Allows Detection of an Active Metabolite of Itraconazole

Maki

Watabe

Iguchi

et al. 2006

Microbiology and Immunology

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To establish an in vitro method of predicting in vivo efficacy of antifungal drugs against Candida albicans and Aspergillus fumigatus, the antifungal activities of fluconazole, itraconazole, and amphotericin B were determined in mouse serum. The minimum inhibitory concentration (MIC) of each drug was measured using mouse serum as a diluent. For C. albicans, the assay endpoint of azoles was defined as inhibition of mycelial extension (mMIC) and for A. fumigatus, as no growth (MIC). The MICs of amphotericin B for both pathogens were defined as the MIC at which no mycelial growth occurred. Serum MIC or mMIC determinations were then used to estimate the concentration of the drugs in serum of mice treated with antifungal drugs by multiplying the antifungal titer of the serum samples by the serum (m)MIC. The serum drug concentrations were also determined by HPLC. The serum concentrations estimated microbiologically showed good agreement with those determined by HPLC, except for itraconazole. Analysis of the serum samples from itraconazole‐treated mice by a sensitive bioautography revealed the presence of additional spots, not seen in control samples of itraconazole. The bioautography assay demonstrated that the additional material detected in serum from mice treated with itraconazole was an active metabolite of itraconazole. The data showed that the apparent reduction in the itraconazole serum concentration as determined by HPLC was the result of the formation of an active metabolite, and that the use of a microbiological method to measure serum concentrations of drugs can provide a method for prediction of in vivo efficacy of antifungal drugs.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 57%

Determination of Antifungal Activities in Serum Samples from Mice Treated with Different Antifungal Drugs Allows Detection of an Active Metabolite of Itraconazole

Maki

Watabe

Iguchi

et al. 2006

Microbiology and Immunology

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“…Firstly, the presence of a base layer without the inocula provided easier-to-measure inhibition zones. The described incubation temperatures were 30 °C (Espinel-Ingroff et al, 1977;Odds et al, 1999), 32 °C (Purangioti et al, 1999, 35 °C (Pascual et al, 2007) and 37 °C (Law et al, 1994;Perea et al, 2000). The temperatures tested in the present paper (28 °C and 37 °C) did not yield different results, revealing that both can be used in the experiments.…”

Section: Methods Developmentmentioning

confidence: 66%

Comparison of microbiological assay and HPLC-UV for determination of fluconazole in capsules

Queiroz

Silva

Prado

et al. 2009

Braz. J. Pharm. Sci.

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The development of a specific agar diffusion bioassay for the quantitative determination of fluconazole formulated in capsules was carried out using a strain of Candida albicans ATCC 18804 as the test organism. A prospective validation of the method showed adequate linearity (r 2 =0.9995), precision (R.S.D. = 4.0% for intra-day and 4.5% for inter-day precision) and accuracy (mean recovery = 102.9%). High performance liquid chromatography was chosen as a comparison method for the fluconazole determination. The contents of fluconazole determined by both methods, for four capsule samples, showed a strong correlation, confirmed by Pearson's correlation coefficient value (r = 0.9884). The bioassay is a suitable method for both research and pharmaceutical industry laboratories.Uniterms: Fluconazole/quantitative determination. Microbiological assay/agar diffusion. High performance liquid chromatography.Este trabalho visou ao desenvolvimento e validação de um método microbiológico por difusão em ágar para quantificação de fluconazol em cápsulas utilizando o isolado Candida albicans ATCC 18804 como reagente biológico. O método foi validado e foi verificada linearidade (r 2 =0,9995), precisão (D.P.R. = 4.0% para precisão intra-dia e 4,5% para precisão inter-dia) e exatidão (recuperação média = 102,9%). Concomitantemente, foi realizado o doseamento de fluconazol nas cápsulas por meio de cromatografia líquida de alta eficiência. Os teores encontrados por ambos os métodos demonstraram alta correlação, confirmada pelo Coeficiente de Correlação de Pearson (r = 0,9884). O ensaio microbiológico desenvolvido pode ser considerado ferramenta valiosa tanto para a pesquisa científica quanto para a rotina da indústria farmacêutica.Unitermos: Fluconazol/quantificação. Ensaio microbiológico/por difusão em ágar. Cromatografia líquida de alta eficiência.

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“…A plasma concentration of unchanged itraconazole (ITRA) у250 ng/ml is considered necessary to obtain a therapeutic effect on Aspergillus. 4 However, since hydroxy-itraconazole (OH-ITRA) has a similar antifungal effect to unchanged ITRA, 5 the active fraction is represented by the sum of unchanged ITRA and its active metabolite OH-ITRA with an effective total level of about 1000 ng equivalents/ml. This effective level could be estimated from the effective plasma levels of unchanged ITRA (Ϸ250 ng/ml) 4,6 and metabolic ratio in human plasma between ITRA and OH-ITRA ([OH-ITRA]/[ITRA] Ϸ2).…”

mentioning

confidence: 99%

Pharmacokinetics of itraconazole oral solution in allogeneic bone marrow transplant patients receiving total body irradiation

Michallet

Persat

Kranzhöfer

et al. 1998

Bone Marrow Transplant

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Summary:A prospective study of the pharmacokinetics of itraconazole solution was performed in 11 patients who underwent allogeneic BMT (day of BMT = day 0) after a conditioning regimen including total body irradiation (TBI). Itraconazole solution (400 mg once a day) was given 7 days before BMT and continued up to the end of neutropenia unless another antifungal treatment was necessary. Blood samples were collected before itraconazole intake (C min ) and 4 h later (C max ) every other day for assays of itraconazole (ITRA) and its active metabolite hydroxy-itraconazole (OH-ITRA). The mean values of C min ITRA and OH-ITRA, respectively, were 287 ؎ 109 ng/ml and 629 ؎ 227 ng/ml at day ؊1 and 378 ؎ 147 ng/ml and 725 ؎ 242 ng/ml at day +1. The maximum C min values were observed at day +3. Six patients at day ؊1 (54%) and 8 at day +1 (72%) had satisfactory residual plasma concentrations of at least 250 ng/ml of unchanged ITRA. From day +1 to day +9, eight patients discontinued the itraconazole treatment, five of them had satisfactory plasma residual concentrations at this time. This work shows a good bioavailability of itraconazole oral solution during the early phase after allogeneic BMT, but more data are needed for the late phases. Keywords: pharmacokinetics; itraconazole solution; BMT; TBI Prophylaxis and treatment of systemic fungal infections in patients undergoing allogeneic bone marrow transplant (BMT) remain important issues. Broad spectrum antifungals with a low toxicity and good bioavailability are being sought. Ideally, orally administered medications given to prevent invasive aspergillosis should provide a systemic effect. However several factors are likely to impair bioavailability of orally administered medications in allogeneic BMT patients: nausea and vomiting mainly during conditioning regimen period, mucositis during aplasia and acute graft-versus-host disease (GVHD) later.Itraconazole, a triazole broad spectrum antifungal 1,2 is presently marketed as capsules. Important variations in plasma itraconazole concentrations observed in patients, compared with healthy volunteers, 3 are related to individual conditions of drug absorption, thereby justifying plasma measurements. A plasma concentration of unchanged itraconazole (ITRA) у250 ng/ml is considered necessary to obtain a therapeutic effect on Aspergillus. 4 However, since hydroxy-itraconazole (OH-ITRA) has a similar antifungal effect to unchanged ITRA, 5 the active fraction is represented by the sum of unchanged ITRA and its active metabolite OH-ITRA with an effective total level of about 1000 ng equivalents/ml. This effective level could be estimated from the effective plasma levels of unchanged ITRA (Ϸ250 ng/ml) 4,6 and metabolic ratio in human plasma between ITRA and OH-ITRA ([OH-ITRA]/[ITRA] Ϸ2). 7 However the capsule formulation is of limited use in allogeneic BMT: its bioavailability is reduced when administered under fasting conditions and when coadministered with antacids. 8 Itraconazole oral solution is a new formulation where ITRA is solub...

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Bioassay for serum itraconazole concentrations using hydroxyitraconazole standards

Cited by 54 publications

References 13 publications

Determination of Antifungal Activities in Serum Samples from Mice Treated with Different Antifungal Drugs Allows Detection of an Active Metabolite of Itraconazole

Determination of Antifungal Activities in Serum Samples from Mice Treated with Different Antifungal Drugs Allows Detection of an Active Metabolite of Itraconazole

Comparison of microbiological assay and HPLC-UV for determination of fluconazole in capsules

Pharmacokinetics of itraconazole oral solution in allogeneic bone marrow transplant patients receiving total body irradiation

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