Wasan K M, Lopez-Berestein G
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Canada.
Eur J Clin Microbiol Infect Dis. 1997 Jan;16(1):81-92. doi: 10.1007/BF01575125.
Patients with cancer and infectious disease often display dyslipidemias that result in changes in their plasma lipoprotein-lipid composition. It is likely that the interactions of liposomal polyenes with plasma lipoproteins may be responsible for the far different pharmacokinetics and pharmacodynamics of these compounds when they are administered to infected patients rather than to animals or healthy volunteers. Amphotericin B (AmpB) and nystatin are examples of such polyenes. Amphotericin B initially distributes with the high-density lipoprotein (HDL) fraction upon incubation in plasma. Over time, AmpB redistributes from HDLs to low-density lipoproteins (LDLs). This redistribution appears to be regulated by lipid transfer protein. However, when AmpB is incorporated into liposomes composed of negatively or positively charged phospholipids, not only is the capability of LTP to transfer AmpB from HDL to LDL diminished, but AmpB remains retained with only the HDL fraction. However, when liposomal nystatin is incubated in plasma, over 50% of nystatin distributes with HDLs. Over time, nystatin redistributes from HDL to the lipoprotein-deficient plasma fraction, which is composed of mainly aqueous plasma proteins. The lipid composition selected for the drug appears to be a vital constituent in regulating the drug's interaction with biological fluids. Furthermore, liposome (or liposomal particle) size, fluidity, and other physiochemical characteristics also play a role in altering the pharmacokinetics and pharmacological effects of lipid-based drug formulations. Armed with this understanding, a rational approach to clinical development of these formulations could be facilitated.
癌症和传染病患者常常出现血脂异常，导致其血浆脂蛋白 - 脂质组成发生变化。当脂质体多烯类药物施用于感染患者而非动物或健康志愿者时，其药代动力学和药效学存在显著差异，这可能与脂质体多烯类药物与血浆脂蛋白的相互作用有关。两性霉素B（AmpB）和制霉菌素就是这类多烯类药物的例子。两性霉素B在血浆中孵育时最初与高密度脂蛋白（HDL）部分分布在一起。随着时间的推移，AmpB从HDL重新分布到低密度脂蛋白（LDL）。这种重新分布似乎受脂质转运蛋白调节。然而，当AmpB被掺入由带负电荷或正电荷的磷脂组成的脂质体中时，脂质转运蛋白（LTP）将AmpB从HDL转移到LDL的能力不仅减弱，而且AmpB仅保留在HDL部分。然而，当脂质体制霉菌素在血浆中孵育时，超过50%的制霉菌素与HDL分布在一起。随着时间的推移，制霉菌素从HDL重新分布到脂蛋白缺乏的血浆部分，该部分主要由血浆水性蛋白组成。所选药物的脂质组成似乎是调节药物与生物流体相互作用的关键成分。此外，脂质体（或脂质体颗粒）的大小、流动性和其他物理化学特性在改变基于脂质的药物制剂的药代动力学和药理作用方面也发挥着作用。基于这种认识，有助于对这些制剂进行合理的临床开发。
