Comparative drug disposition, urinary pharmacokinetics, and renal effects of multilamellar liposomal nystatin and amphotericin B deoxycholate in rabbits

被引:12
作者
Groll, AH
Mickiene, D
Petraitis, V
Petraitiene, R
Alfaro, RM
King, C
Piscitelli, SC
Walsh, TJ
机构
[1] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA
[2] NIH, Warren G Magnuson Clin Ctr, Dept Pharm, Pharmacokinet Res Lab, Bethesda, MD 20892 USA
[3] NIH, Warren G Magnuson Clin Ctr, Dept Clin Pathol, Bethesda, MD 20892 USA
[4] Univ Munster, Childrens Hosp, Dept Pediat Hematol Oncol, D-4400 Munster, Germany
[5] Univ Munster, Childrens Hosp, Ctr Bone Marrow Transplantat, Infect Dis Res Program, D-4400 Munster, Germany
关键词
D O I
10.1128/AAC.47.12.3917-3925.2003
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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 mug/ml for LNYS versus 3.36 mug/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 μg . h/ml for LNYS versus 12 μg . 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 less than or equal to 8-fold-smaller volume of distribution at steady state (P = 0.002). Urinary drug concentration data revealed a greater than or equal to 10-fold-higher C-max (16 to 10 mug/ml for LNYS versus 0.96 mug/ml for DAMB; P = 0.015) and a 4- to 7-fold-greater AUC(0-24) (63 to 35 mug . h/ml for LNYS versus 8.9 mug . h/ml for DAMB; P = 0.015) following the administration of LNYS, with a dose-dependent decrease in the dose-normalized 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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收藏
页码:3917 / 3925
页数:9
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