MODIFICATIONS IN HIGH-DENSITY-LIPOPROTEIN LIPID-COMPOSITION AND STRUCTURE ALTER THE PLASMA DISTRIBUTION OF FREE AND LIPOSOMAL ANNAMYCIN

Recent studies have shown that changes in lipoprotein cholesterol and triglyceride concentration alters the plasma distribution of free (Ann .) and liposomal annamycin (LAnn) and that the majority of Ann. is ass ociated with high-density lipoproteins (HDL) following the incubation in plasma of LAnn. To demonstrate that alterations in HDL lipid compos ition and HDL structure may influence the plasma distribution of Ann, and LAnn, Ann. and LAnn (20 mu g/mL) were incubated in plasma pretreat ed with dithionitrobenzoate (DTNB, a compound which inhibits the conve rsion of free cholesterol to esterified cholesterol) 18 h prior to the experiment or in untreated plasma for 60 min at 37 degrees C. In addi tion, Ann. and LAnn were co-incubated with DTNB in plasma for 60 min a t 37 SC. Following incubation the plasma was separated into its HDL, l ow-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), and lipoprotein-deficient plasma (LPDP) fractions by ultracentrifugation and as sayed for Ann. by fluorimetry. The HDL plasma cholesterol:trigl yceride concentration ratio was significantly decreased following 18 h of DTNB pretreatment compared to untreated plasma controls. No signif icant differences in LDL/VLDL plasma cholesterol:triglyceride concentr ation ratio following 18 h of DTNB pretreatment was observed. An incre ased number of discoidal HDL particles were observed following 18 h of DTNB pretreatment. When Ann. was incubated in plasma pretreated with DTNB for 18 h the percentage of Ann. recovered in the HDL, LDL, and VL DL fractions significantly increased, However, the percentage of Ann, recovered within the LPDP fraction was significantly decreased. When L Ann was incubated in plasma pretreated with DTNB for 18 h the percenta ge of Ann. recovered in the HDL fraction significantly decreased, The percentage of Ann. recovered in the LPDP fraction significantly increa sed when LAnn was incubated in plasma pretreated with DTNB for 18 h. N o significant differences in Ann, lipoprotein distribution were observ ed when Ann, and LAnn were co-incubated with DTNB in plasma for 1 h, T hese findings suggest that the cholesterol:triglyceride concentration ratio and physical structure of HDL maybe important in defining the ca pacity of HDL to sequester Ann.