Wasan K M, Kennedy A L, Cassidy S M, Ramaswamy M, Holtorf L, Chou J W, Pritchard P H
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
Antimicrob Agents Chemother. 1998 Dec;42(12):3146-52. doi: 10.1128/AAC.42.12.3146.
The purpose of this study was to determine if a relationship exists among total serum and lipoprotein cholesterol concentration, the severity of amphotericin B (AmpB)-induced renal toxicity, and the serum pharmacokinetics of AmpB in hypercholesterolemic rabbits administered AmpB and AmpB lipid complex (ABLC). After 10 days of cholesterol-enriched diet (0.50% [wt/vol]) or regular rabbit diet (control), each rabbit was administered a single intravenous bolus of AmpB or ABLC (1.0 mg/kg of body weight). Blood samples were obtained before administration and serially thereafter for the assessment of serum pharmacokinetics, kidney toxicity, and serum lipoprotein distribution. Rabbits were humanely sacrificed after all blood samples were obtained, and tissues were harvested for drug analysis. Before drug treatment, cholesterol-fed rabbits demonstrated marked increases in total serum cholesterol and low-density lipoprotein (LDL) cholesterol levels compared with levels in rabbits on a regular diet. No significant differences in triglyceride levels were observed. A significant increase in serum creatinine levels was observed in cholesterol-fed and regular diet-fed rabbits administered AmpB. However, the magnitude of this increase was 2.5-fold greater in cholesterol-fed rabbits than in regular diet-fed rabbits. No significant differences in triglyceride levels were observed. A significant increase in serum creatinine levels was observed in cholesterol-fed and regular diet-fed rabbits administered ABLC. Whereas AmpB pharmacokinetics were significantly altered in cholesterol-fed rabbits administered free AmpB, similar AmpB pharmacokinetics were observed in both rabbit groups administered ABLC. Renal AmpB levels were significantly increased in cholesterol-fed rabbits administered AmpB compared with those in all other groups. Hepatic and lung AmpB levels were elevated in cholesterol-fed rabbits administered free AmpB compared to controls. In addition, hepatic, lung, and spleen AmpB levels were significantly decreased in cholesterol-fed rabbits administered ABLC compared to controls. An increased percentage of AmpB was recovered in LDL-very-low-density lipoprotein fraction when free AmpB was administered to cholesterol-fed rabbits compared with those in all other groups. These findings suggest that increases in cholesterol, specifically, LDL cholesterol levels, modify the disposition and renal toxicity of free AmpB. However, the pharmacokinetics and renal toxicity of ABLC were independent of elevations in total and LDL cholesterol levels.
本研究的目的是确定在给予两性霉素B（AmpB）和两性霉素B脂质复合物（ABLC）的高胆固醇血症兔中，血清总胆固醇和脂蛋白胆固醇浓度、AmpB诱导的肾毒性严重程度以及AmpB的血清药代动力学之间是否存在关联。在给予富含胆固醇的饮食（0.50%[重量/体积]）10天或常规兔饲料（对照）后，每只兔静脉注射一次AmpB或ABLC（1.0mg/kg体重）。给药前及给药后连续采集血样，以评估血清药代动力学、肾毒性和血清脂蛋白分布。采集完所有血样后，对兔实施安乐死，并采集组织进行药物分析。在药物治疗前，与常规饮食的兔相比，喂食胆固醇的兔血清总胆固醇和低密度脂蛋白（LDL）胆固醇水平显著升高。未观察到甘油三酯水平有显著差异。给予AmpB的喂食胆固醇和常规饮食的兔血清肌酐水平均显著升高。然而，喂食胆固醇的兔的升高幅度比喂食常规饮食的兔大2.5倍。未观察到甘油三酯水平有显著差异。给予ABLC的喂食胆固醇和常规饮食的兔血清肌酐水平均显著升高。虽然给予游离AmpB的喂食胆固醇的兔的AmpB药代动力学有显著改变，但给予ABLC的两组兔的AmpB药代动力学相似。给予AmpB的喂食胆固醇的兔的肾AmpB水平比所有其他组的兔显著升高。与对照组相比，给予游离AmpB的喂食胆固醇的兔的肝和肺AmpB水平升高。此外，与对照组相比，给予ABLC的喂食胆固醇的兔的肝、肺和脾AmpB水平显著降低。与所有其他组相比，给予游离AmpB的喂食胆固醇的兔在LDL-极低密度脂蛋白组分中回收的AmpB百分比增加。这些发现表明，胆固醇升高，特别是LDL胆固醇水平升高，会改变游离AmpB的处置和肾毒性。然而，ABLC的药代动力学和肾毒性与总胆固醇和LDL胆固醇水平的升高无关。
