Modifications in plasma lipoprotein concentration and lipid composition regulate the biological activity of...

The maximum tolerated dose and pharmacokinetics of a drug is usually determined in healthy human volunteers and animals. This data is then used to define the dosing recommendation for the diseased patient population. However, in the case of some hydrophobic drugs, the dose which is deemed nontoxic becomes ineffective and/or toxic when administered to the diseased patient. This observation might be explained by several lines of evidence which indicate that binding of drugs such as amphotericin B (AmpB) and cyclosporine (CSA) to plasma low-density lipoprotein- (LDL) cholesterol is involved in the development of kidney toxicity. Our preliminary studies have suggested that this phenomena might be due to increase lipid transfer protein (LTP 1) activity which promotes the transfer of AmpB from high-density lipoproteins to LDL. In addition, since LTP 1 function is regulated by the lipid content of plasma lipoproteins, we suggest that changes in lipoprotein composition that occur in dyslipidemia regulate the distribution of these and other hydrophobic drugs (i.e., annamycin and nystatin). The impact of these studies on hydrophobic drug therapy could have broad implications on how we evaluate and determine dosing of hydrophobic drugs in dyslipidemic patients. By understanding the mechanism(s) responsible for the distribution of hydrophobic compounds in the bloodstream, we are trying to define the effect of dyslipidemias on the plasma clearance and therapeutic index of hydrophobic compounds.