High-performance liquid chromatographic determination of liposomal nystatin in plasma and tissues for pharmacokinetic and tissue distribution studies

Groll, Andreas H.; Mickiene, Diana; Werner, Kathy; Piscitelli, Stephen C.; Walsh, Thomas J.

doi:10.1016/s0378-4347(99)00396-5

Cited by 34 publications

(25 citation statements)

References 11 publications

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“…Concentrations of nystatin and amphotericin B were determined as total drug concentrations by reversed-phase HPLC and by using bulk nystatin (Gist-Procades) and amphotericin B (Sigma) as reference standards as previously described (14,17).…”

Section: Methodsmentioning

confidence: 99%

Comparative Drug Disposition, UrinaryPharmacokinetics, and Renal Effects of Multilamellar Liposomal Nystatinand Amphotericin B Deoxycholate inRabbits

Groll

Mickiene

Petraitis

et al. 2003

Antimicrob Agents Chemother

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The comparative drug dispositions, urinary pharmacokinetics, and effects on renal function of multilamellar liposomal nystatin (LNYS; Nyotran) and amphotericin B deoxycholate (DAMB; Fungizone) were studied in rabbits. Drug concentrations were determined by high-performance liquid chromatography as total concentrations of LNYS and DAMB. In comparison to a standard dose of 1 mg of DAMB/kg of body weight, therapeutic dosages of LNYS, i.e., 2, 4, and 6 mg/kg, resulted in escalating maximum concentrations (C max ) (17 to 56 g/ml for LNYS versus 3.36 g/ml for DAMB; P < 0.001) and values for the area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) (17 to 77 g ⅐ h/ml for LNYS versus 12 g ⅐ h/ml for DAMB; P < 0.001) in plasma but a significantly faster total clearance from plasma (0.117 to 0.080 liter/h/kg for LNYS versus 0.055 liter/h/kg for DAMB; P ‫؍‬ 0.013) and a <8-fold-smaller volume of distribution at steady state (P ‫؍‬ 0.002). Urinary drug concentration data revealed a >10-fold-higher C max (16 to 10 g/ml for LNYS versus 0.96 g/ml for DAMB; P ‫؍‬ 0.015) and a 4-to 7-fold-greater AUC 0-24 (63 to 35 g ⅐ h/ml for LNYS versus 8.9 g ⅐ h/ml for DAMB; P ‫؍‬ 0.015) following the administration of LNYS, with a dose-dependent decrease in the dosenormalized AUC 0-24 in urine (P ‫؍‬ 0.001) and a trend toward a dose-dependent decrease in renal clearance. Except for the kidneys, the mean concentrations of LNYS in liver, spleen, and lung 24 h after dosing were severalfold lower than those after administration of DAMB (P, <0.002 to <0.001). Less than 1% each of the total dose of LNYS was recovered from the kidneys, liver, spleen, and lungs; in contrast, a quarter of the total dose was recovered from the livers of DAMB-treated animals. LNYS had dose-dependent effects on glomerular filtration and distal, but not proximal, renal tubular function which did not exceed those of DAMB at the highest investigated dosage of 6 mg/kg. The results of this experimental study demonstrate fundamental differences in the dispositions of LNYS and DAMB. Based on its enhanced urinary exposure, LNYS may offer a therapeutic advantage in systemic fungal infections involving the upper and lower urinary tracts that require therapy with antifungal polyenes.

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Section: Methodsmentioning

confidence: 99%

Comparative Drug Disposition, UrinaryPharmacokinetics, and Renal Effects of Multilamellar Liposomal Nystatinand Amphotericin B Deoxycholate inRabbits

Groll

Mickiene

Petraitis

et al. 2003

Antimicrob Agents Chemother

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“…F-88, p. 161,1997). This has prompted new investigations of its antifungal properties and spectrum as well as its physicochemical and pharmacokinetic characteristics (5,7,11,15; S. Arikan, M. Lozano-Chiu, V. Paetznick, D. Gordon, T. Wallace, and J. H. Rex, Abstr. 98th Gen. Meet.…”

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confidence: 99%

Differential Antifungal Activity of Isomeric Forms of Nystatin

Ostrosky-Zeichner

Bazemore

Paetznick

et al. 2001

Antimicrob Agents Chemother

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When nystatin is placed in RPMI and other biological fluids, there is loss of pure nystatin, with the development of two distinguishable chromatographic peaks, 1 and 2. Peak 1 appears identical to commercially prepared nystatin. By nuclear magnetic resonance (NMR) and mass spectral analysis, peak 2 appears to be an isomer of peak 1. The isomers are quantitatively and fully interconvertible. Formation of peak 2 is accelerated at a pH of >7.0 and ultimately reaches a near 55:45 (peak 1/peak 2 ratio) mixture. We sought to determine the relative activities of peaks 1 and 2 against Candida spp. Peak 2 consistently showed higher MICs when it was the predominant form during the experiment. Time-kill analyses showed that peak 2 required >8؋ the concentration of peak 1 to produce a modest and delayed killing effect, which was never of the same magnitude as that produced by peak 1. In both types of assays, the activity of peak 2 corresponded with intra-assay formation of peak 1. Both MIC measurements and time-kill analysis suggest that peak 2 has considerably less activity, if any at all, against Candida spp. Peak 2 may serve as a reservoir for peak 1.Life-threatening fungal infections have become increasingly prevalent among patients with human immunodeficiency virus or AIDS, patients with cancer, transplant recipients, and patients in intensive care units (1, 2-4, 6, 10). Therapeutic options are often limited by the toxicity of currently available systemic antifungal agents and the emergence of resistance (9,24,25). This has prompted the development of new antifungal agents, as well as the "rediscovery" and "reengineering" of agents where use had been limited due to toxicity (16).Nystatin is a polyene-macrolide antifungal antibiotic produced by Streptomyces noursei that was discovered and developed in the 1950s (18). It is now widely available for the topical treatment of localized fungal infections. Toxicity problems prevented its use as a systemic agent, but recently developed liposomal delivery technologies have made it an attractive candidate for the treatment of severe systemic fungal infections (12,16,17,20,26; C. J. Jessup, T. J. Wallace, and M. A. Ghannoum, 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-88, p. 161, 1997). This has prompted new investigations of its antifungal properties and spectrum as well as its physicochemical and pharmacokinetic characteristics (5, 7, 11, 15; S. Arikan, M. Lozano-Chiu, V. Paetznick, D. Gordon, T. Wallace, and J. H. Rex, Abstr. 98th Gen. Meet. Am. Society Microbiol., abstr. C-280, p. 178, 1998).Commercially prepared nystatin appears as a single, highly pure chromatographic peak (hereinafter referred as peak 1) while in an organic solvent. However, when placed in a biological matrix, such as human plasma or culture medium, chromatographic analysis yields a second peak that elutes after the pure peak seen from nystatin stored in an organic solvent. Earlier work (data on file at Aronex Pharmaceuticals) suggested that the appearance of this second peak, termed peak ...

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“…Os resultados obtidos a partir dos testes realizados utilizando diferentes composições para a fase móvel, diferentes colunas cromatográficas, e diferentes solventes, descritos na literatura (Groll, 1999;Liu, 1995;Lopez, 1998;Lambros, 1996), foram avaliados considerando resolução do pico, maior eficiência na determinação do teor e menor interferência dos solventes. Diante disto, a coluna C 18 , fase reversa, Novapak ® , 3,9 x 150 mm, 4 µm foi a selecionada para a execução do ensaio, assim como a composição da fase móvel foi tampão fosfato de sódio monobásico monoidratado 0,25 mM e EDTA dissódico 0,025 mM, pH 6,00±0,05, acetonitrila e metanol (40:30:30).…”

Section: Resultados E Discussão Desenvolvimento Do Método Analíticounclassified

“…A eluição cromatográfica foi realizada com fase móvel composta por tampão fosfato de sódio monobásico monoidratado 0,25 mM e EDTA dissódico FIGURA 1 -Estrutura química da nistatina (Groll et al, 1999). 0,025 mM, pH 6,00±0,05 (ajustado com NaOH 1M) : acetonitrila : metanol (40:30:30), com vazão de 1,0 mL/min.…”

Section: Desenvolvimento Do Método Analíticounclassified

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Desenvolvimento e validação de método analítico para nistatina creme vaginal por cromatografia líquida de alta eficiência

Lavra¹,

Sônego²,

Silva³

et al. 2008

Rev. Bras. Cienc. Farm.

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High-performance liquid chromatographic determination of liposomal nystatin in plasma and tissues for pharmacokinetic and tissue distribution studies

Cited by 34 publications

References 11 publications

Comparative Drug Disposition, UrinaryPharmacokinetics, and Renal Effects of Multilamellar Liposomal Nystatinand Amphotericin B Deoxycholate inRabbits

Comparative Drug Disposition, UrinaryPharmacokinetics, and Renal Effects of Multilamellar Liposomal Nystatinand Amphotericin B Deoxycholate inRabbits

Differential Antifungal Activity of Isomeric Forms of Nystatin

Desenvolvimento e validação de método analítico para nistatina creme vaginal por cromatografia líquida de alta eficiência

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