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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Pharmacokinetic-pharmacodynamic comparison of amphotericin B (AMB) and two lipid-associated AMB preparations, liposomal AMB and AMB lipid complex, in murine candidiasis models.
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Pharmacokinetic-pharmacodynamic comparison of amphotericin B (AMB) and two lipid-associated AMB preparations, liposomal AMB and AMB lipid complex, in murine candidiasis models.

机译：在鼠念珠菌病模型中，两性霉素B（AMB）和两种脂质相关的AMB制剂，脂质体AMB和AMB脂质复合物的药代动力学-药效学比较。

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摘要

It is generally accepted that the lipid formulations of amphotericin B (AMB) are not as potent as conventional AMB on a milligram-per-kilogram basis. We used a neutropenic murine disseminated candidiasis model to compare the in vivo potencies of AMB, liposomal AMB (L-AMB), and AMB lipid complex (ABLC) pharmacodynamically. The pharmacokinetics of the antifungals were examined in serum and in three organs commonly seeded in disseminated candidiasis (kidneys, liver, and lung). Both single-dose time-kill studies and multiple-dosing-regimen studies were used with each of the compounds. Determinations of the numbers of CFU in the kidneys were performed following the administration of three escalating single doses of the polyenes at various times over 48 h. The areas under the time-kill curves (AUTKs) for each dose level of the drugs were compared by analysis of variance (ANOVA). In the multiple-dosing-regimen studies with five Candida isolates, AMB, L-AMB, and ABLC were administered daily for 72 h. The organism burdens in the mouse kidneys were similarly used as the treatment end point. Additional multiple regimen-dosing-studies were performed with a single Candida albicans isolate, and the microbiologic outcomes in four internal organs (kidneys, liver, spleen, and lung) were examined at the end of therapy (48 h). The relationship between the dose and the drug exposure expressed by the pharmacokinetics of the dosing regimens in serum and organ tissue were analyzed by using a maximum-effect model. ANOVA was used to compare the drug exposures necessary to achieve the 25% effective dose (ED25), ED50, ED75, and 1 log10 killing. Comparison of AUTKs suggested that AMB was 4.3- to 5.9-fold more potent than either ABLC or L-AMB. The time-kill curves for both lipid formulations were very similar. In the multiple-dosing-regimen studies, AMB was 5.0- to 8.0-fold more potent than each of the lipid formulations against five Candida isolates in the kidneys. Similar differences in potency (5.1- to 7.2-fold) were observed in the other end organs. The difference in pharmacokinetics in serum accounted for much of the difference in potency between AMB and ABLC (ratio of serum ABLC area under the curve of effective doses to serum AMB area under the curve of effective doses, 1.2). The differences in the kinetics in the various end organs between AMB and L-AMB were better at explaining the disparate potencies at these infection sites (ratio of organ L-AMB area under the curve of effective doses to organ AMB area under the curve of effective doses, 1.1).
机译：通常公认的是，两性霉素B（AMB）的脂质制剂以每千克毫克计的效力不如常规AMB。我们使用中性粒细胞减少的念珠菌散布模型来比较AMB，脂质体AMB（L-AMB）和AMB脂质复合物（ABLC）的体内药效学。在血清中和散播念珠菌病中通常播种的三个器官（肾脏，肝脏和肺脏）中检查了抗真菌药的药代动力学。每种化合物都使用了单剂量时间杀灭研究和多剂量方案研究。在48小时内，在不同时间给予三剂量递增剂量的多烯后，进行肾脏CFU数量的测定。通过方差分析（ANOVA）比较了每种剂量水平的药物在时间杀灭曲线（AUTK）下的面积。在使用五株假丝酵母的多剂量方案研究中，每天服用AMB，L-AMB和ABLC 72小时。小鼠肾脏中的生物负荷类似地用作治疗终点。用一个白色念珠菌分离物进行了另外的多种方案剂量研究，并且在治疗结束时（48小时）检查了四个内部器官（肾脏，肝脏，脾脏和肺脏）的微生物学结果。通过使用最大效应模型分析了由剂量方案在血清和器官组织中的药代动力学表达的剂量与药物暴露之间的关系。使用ANOVA比较达到25％有效剂量（ED25），ED50，ED75和1 log10杀伤率所需的药物暴露。 AUTK的比较表明，AMB的效力比ABLC或L-AMB高4.3到5.9倍。两种脂质制剂的时间杀伤曲线非常相似。在多剂量方案研究中，针对肾脏中五种念珠菌分离物，AMB的效力比每种脂质制剂高5.0至8.0倍。在其他末端器官中观察到相似的效价差异（5.1-7.2倍）。血清药代动力学的差异是AMB和ABLC之间效力差异的主要原因（有效剂量曲线下的血清ABLC面积与有效剂量曲线下的血清AMB面积之比1.2）。 AMB和L-AMB之间各个终末器官动力学的差异更好地解释了这些感染部位的不同效力（有效剂量曲线下的器官L-AMB面积比有效剂量曲线下的器官AMB面积比）剂量，1.1）。

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