Ramaswamy M, Wallace T L, Cossum P A, Wasan K M
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
Antimicrob Agents Chemother. 1999 Jun;43(6):1424-8. doi: 10.1128/AAC.43.6.1424.
The objective of this study was an interspecies comparison of free nystatin (NYS) and liposomal NYS (Nyotran) distribution in plasma. NYS and liposomal NYS at concentrations of 5, 10, and 20 microg of NYS/ml were incubated in human, dog, and rat plasma for 5, 60, and 180 min at 37 degrees C. Following these incubations, plasma samples were separated into their high-density lipoprotein (HDL), triglyceride-rich lipoprotein, low-density lipoprotein, and lipoprotein-deficient plasma (LPDP) fractions by density-gradient ultracentrifugation, and each fraction was assayed for NYS by high-pressure liquid chromatography. Total plasma and lipoprotein cholesterol, triglyceride, and protein concentrations in each human, dog, or rat plasma sample were determined by enzymatic assays. When NYS and liposomal NYS were incubated in human, dog, or rat plasma, the majority of the NYS was recovered in the LPDP fraction. For the 5- and 60-min incubation times for all plasmas measured, a significantly greater percentage of NYS was recovered in the lipoprotein fraction (primarily HDL) following the incubation of liposomal NYS than following the incubation of NYS. There was a significant correlation between the lipoprotein lipid and protein profiles in human, dog, and rat plasmas and the distribution of NYS and liposomal NYS in plasma. In particular, differences in the proportion of plasma lipoprotein cholesterol, triglyceride, and apolar lipids (cholesteryl ester and triglycerides) carried by HDL influenced the distribution of NYS and liposomal NYS within plasmas of different species. These findings suggest that the distribution of NYS among plasma lipoproteins of different species is defined by the proportion of lipid carried by HDL, and this is possibly an important consideration when evaluating the pharmacokinetics, toxicities, and activities of these compounds following administration to different animal species.
本研究的目的是对游离制霉菌素（NYS）和脂质体制霉菌素（Nyotran）在血浆中的分布进行种间比较。将浓度为5、10和20微克NYS/毫升的NYS和脂质体制霉菌素在人、狗和大鼠血浆中于37℃孵育5、60和180分钟。孵育后，通过密度梯度超速离心将血浆样本分离为高密度脂蛋白（HDL）、富含甘油三酯的脂蛋白、低密度脂蛋白和脂蛋白缺乏血浆（LPDP）组分，并用高压液相色谱法测定各组分中的NYS。通过酶法测定每个人、狗或大鼠血浆样本中的总血浆和脂蛋白胆固醇、甘油三酯和蛋白质浓度。当NYS和脂质体制霉菌素在人、狗或大鼠血浆中孵育时，大部分NYS在LPDP组分中回收。对于所有测定血浆的5分钟和60分钟孵育时间，脂质体制霉菌素孵育后在脂蛋白组分（主要是HDL）中回收的NYS百分比显著高于NYS孵育后。人、狗和大鼠血浆中的脂蛋白脂质和蛋白质谱与NYS和脂质体制霉菌素在血浆中的分布之间存在显著相关性。特别是，HDL携带的血浆脂蛋白胆固醇、甘油三酯和非极性脂质（胆固醇酯和甘油三酯）比例的差异影响了不同物种血浆中NYS和脂质体制霉菌素的分布。这些发现表明，NYS在不同物种血浆脂蛋白中的分布由HDL携带的脂质比例决定，这可能是在评估这些化合物给予不同动物物种后的药代动力学、毒性和活性时的一个重要考虑因素。
