Diversity of lipid-based polyene formulations and their behavior in biological systems.
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.
Wasan
K M
KM
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Canada.
Lopez-Berestein
G
G
D000666:Amphotericin B / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D016867:Immunocompromised Host; D007668:Kidney / Q000187:drug effects; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism; D008081:Liposomes; D009181:Mycoses / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D009761:Nystatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D010586:Phagocytes / Q000187:drug effects
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D008074:Lipoproteins; D008081:Liposomes; D009761:Nystatin; D000666:Amphotericin B