Compartmental pharmacokinetics and tissue distribution of multilamellar liposomal nystatin in rabbits

Andreas H. Groll, Diana Mickiene, Kathy Werner, Ruta Petraitiene, Vidmantas Petraitis, Myrna Calendario, Aida Field-Ridley, Jeremy Crisp, Stephen C. Piscitelli, Thomas J. Walsh

Research output: Contribution to journalArticle

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Abstract

The plasma pharmacokinetics of multilamellar liposomal nystatin were studied in normal, catheterized rabbits after single and multiple daily intravenous administration of dosages of 2, 4, and 6 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of liposomal nystatin were measured as those of nystatin by a validated high-performance liquid chromatography method, and plasma concentration data were fitted into a two-compartment open model. Across the investigated dosage range, liposomal nystatin demonstrated nonlinear kinetics with more than proportional increases in the AUC0-24 and decreasing clearance, consistent with dose-dependent tissue distribution and/or a dose- dependent elimination process. After single-dose administration, the mean C(max) increased from 13.07 μg/ml at 2 mg/kg to 41.91 μg/ml at 6 mg/kg (P < 0.001); the AUC0-24 changed from 11.65 to 67.44 μg · h/ml (P < 0.001), the V(d) changed from 0.205 to 0.184 liters/kg (not significant), the CL(i) from 0.173 to 0.101 liters/kg · h (P < 0.05), and terminal half-life from 0.96 to 1.51 h (P < 0.05). There were no significant changes in pharmacokinetic parameters after multiple dosing over 14 days. Assessment of tissue concentrations of nystatin near peak plasma levels after multiple dosing over 15 days revealed preferential distribution to the lungs, liver, and spleen at that time point. Substantial levels were also found in the urine, raising the possibility that renal excretion may play a significant role in drug elimination. Liposomal nystatin administered to rabbits was well tolerated and displayed nonlinear pharmacokinetics, potentially therapeutic peak plasma concentrations, and substantial penetration into tissues. Pharmacokinetic parameters were very similar to those observed in patients, thus validating results derived from infection models in the rabbit and allowing inferences to be made about the treatment of invasive fungal infections in humans.

Original languageEnglish (US)
Pages (from-to)950-957
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume44
Issue number4
DOIs
StatePublished - Apr 2000
Externally publishedYes

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Nystatin
Tissue Distribution
Pharmacokinetics
Rabbits
Pharmaceutical Preparations
Intravenous Administration
Half-Life
Spleen
High Pressure Liquid Chromatography
Body Weight
Urine
Lung
Liver
Therapeutics
Infection

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Groll, A. H., Mickiene, D., Werner, K., Petraitiene, R., Petraitis, V., Calendario, M., ... Walsh, T. J. (2000). Compartmental pharmacokinetics and tissue distribution of multilamellar liposomal nystatin in rabbits. Antimicrobial Agents and Chemotherapy, 44(4), 950-957. https://doi.org/10.1128/AAC.44.4.950-957.2000

Compartmental pharmacokinetics and tissue distribution of multilamellar liposomal nystatin in rabbits. / Groll, Andreas H.; Mickiene, Diana; Werner, Kathy; Petraitiene, Ruta; Petraitis, Vidmantas; Calendario, Myrna; Field-Ridley, Aida; Crisp, Jeremy; Piscitelli, Stephen C.; Walsh, Thomas J.

In: Antimicrobial Agents and Chemotherapy, Vol. 44, No. 4, 04.2000, p. 950-957.

Research output: Contribution to journalArticle

Groll, AH, Mickiene, D, Werner, K, Petraitiene, R, Petraitis, V, Calendario, M, Field-Ridley, A, Crisp, J, Piscitelli, SC & Walsh, TJ 2000, 'Compartmental pharmacokinetics and tissue distribution of multilamellar liposomal nystatin in rabbits', Antimicrobial Agents and Chemotherapy, vol. 44, no. 4, pp. 950-957. https://doi.org/10.1128/AAC.44.4.950-957.2000
Groll, Andreas H. ; Mickiene, Diana ; Werner, Kathy ; Petraitiene, Ruta ; Petraitis, Vidmantas ; Calendario, Myrna ; Field-Ridley, Aida ; Crisp, Jeremy ; Piscitelli, Stephen C. ; Walsh, Thomas J. / Compartmental pharmacokinetics and tissue distribution of multilamellar liposomal nystatin in rabbits. In: Antimicrobial Agents and Chemotherapy. 2000 ; Vol. 44, No. 4. pp. 950-957.
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abstract = "The plasma pharmacokinetics of multilamellar liposomal nystatin were studied in normal, catheterized rabbits after single and multiple daily intravenous administration of dosages of 2, 4, and 6 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of liposomal nystatin were measured as those of nystatin by a validated high-performance liquid chromatography method, and plasma concentration data were fitted into a two-compartment open model. Across the investigated dosage range, liposomal nystatin demonstrated nonlinear kinetics with more than proportional increases in the AUC0-24 and decreasing clearance, consistent with dose-dependent tissue distribution and/or a dose- dependent elimination process. After single-dose administration, the mean C(max) increased from 13.07 μg/ml at 2 mg/kg to 41.91 μg/ml at 6 mg/kg (P < 0.001); the AUC0-24 changed from 11.65 to 67.44 μg · h/ml (P < 0.001), the V(d) changed from 0.205 to 0.184 liters/kg (not significant), the CL(i) from 0.173 to 0.101 liters/kg · h (P < 0.05), and terminal half-life from 0.96 to 1.51 h (P < 0.05). There were no significant changes in pharmacokinetic parameters after multiple dosing over 14 days. Assessment of tissue concentrations of nystatin near peak plasma levels after multiple dosing over 15 days revealed preferential distribution to the lungs, liver, and spleen at that time point. Substantial levels were also found in the urine, raising the possibility that renal excretion may play a significant role in drug elimination. Liposomal nystatin administered to rabbits was well tolerated and displayed nonlinear pharmacokinetics, potentially therapeutic peak plasma concentrations, and substantial penetration into tissues. Pharmacokinetic parameters were very similar to those observed in patients, thus validating results derived from infection models in the rabbit and allowing inferences to be made about the treatment of invasive fungal infections in humans.",
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