MODIFICATIONS IN PLASMA-LIPOPROTEIN CONCENTRATION AND LIPID-COMPOSITION REGULATE THE BIOLOGICAL-ACTIVITY OF HYDROPHOBIC DRUGS

The maximum tolerated dose and pharmacokinetics of a drug is usually d etermined in healthy human volunteers and animals. This data is then u sed to define the dosing recommendation for the diseased patient popul ation. 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 severa l lines of evidence which indicate that binding of drugs such as ampho tericin B (AmpB) and cyclosporine (CSA) to plasma low-density lipoprot ein- (LDL) cholesterol is involved in the development of kidney toxici ty. Our preliminary studies have suggested that this phenomena might b e due to increase lipid transfer protein (LTP 1) activity which promot es the transfer of AmpB from high-density lipoproteins to LDL. In addi tion, 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 hy drophobic drugs (i.e., annamycin and nystatin). The impact of these st udies 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 distr ibution of hydrophobic compounds in the bloodstream, we are trying to define the effect of dyslipidemias on the plasma clearance and therape utic index of hydrophobic compounds.