The influences of Intralipid (IL) and 0.45% normal-saline infusions on the concentration in serum and distribution in tissue of amphotericin B (AmpB) and liposomal amphotericin B (L-AmpB) in rats were compared. In animals receiving a continuous IL infusion, concentrations of AmpB in kidneys and lungs were significantly higher, but the concentration of AmpB in serum was significantly lower in animals administered AmpB versus those given L-AmpB. In animals receiving a continuous normal-saline infusion concentrations of AmpB in kidneys and the spleen were significantly higher, but the concentration of AmpB in serum was significantly lower in animals administered AmpB versus those given L-AmpB. These results suggest that the increased total serum cholesterol and high-density lipoprotein cholesterol during the IL infusion decreased the clearance of AmpB from the bloodstream and decreased the L-AmpB concentration in the kidney and lung.Amphotericin B (AmpB) remains one of the most effective and widely used agents in the treatment of systemic fungal infections; however, its use is limited by dose-dependent nephrotoxicity (3). When AmpB is incorporated into liposomes composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) (7:3, wt/wt) with a lipid-to-drug ratio of 10:1, wt/wt, it is as effective as, but less toxic than, Fungizone (which consists of AmpB and desoxycholate in a 5:4, wt/wt, ratio) in experimental animal models (9, 10) and patients (8) with systemic fungal infections. However, the mechanisms that result in the enhanced therapeutic index of liposomal AmpB (L-AmpB) are not fully understood.Previous pharmacokinetic and tissue distribution studies have described AmpB's disposition in the body as having a central compartment and two peripheral compartments (2).AmpB and L-AmpB have a large volume of distribution in humans as a result of high accumulation within tissues, and AmpB has a long terminal half-life, 15 days (2), probably due to the slow release of the drug from tissue sites.We have demonstrated a smaller area under the serum AmpB concentration-time curve, greater volume of distribution at steady state, and faster systemic clearance of AmpB in an induced diabetic murine model which indirectly results in hyperlipidemia and hyperlipoproteinemia versus normolipidemic rats (20). Furthermore, we observed a lower distribution of AmpB in kidney and liver tissues and smaller nephrotoxic effects of AmpB in diabetic rats. However, the pharmacokinetics, tissue distribution, and extents of nephrotoxic effects of L-AmpB in diabetic rats were unchanged (20). In addition, we have demonstrated that AmpB associates predominantly with high-density lipoproteins (HDL) following a 1-h incubation at 37°C in human serum, and the amount of AmpB associated with HDL increases when AmpB is incorporated into negatively charged liposomes composed of DMPC and DMPG (17).

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Changes in erythrocyte polyamine levels during intravenous hyperalimentation in cancer and noncancer patients were determined, and the influence of host nutritional status on polyamine metabolism was analyzed. RBC putrescine (P less than .001), spermidine (P less than .01), and spermine (P less than .005) levels, and the putrescine-spermidine ratio (P less than .001) increased in the cancer group while no significant increases were noted in the noncancer group. The degree of malnutrition, based on body weight loss and plasma albumin, transferrin, prealbumin, and retinol-binding protein levels, was significantly greater in the cancer group than in the noncancer group, giving rise to the possibility that repletion of nutritional deficits in host tissues could have contributed to the rise in RBC polyamines. When cancer patients of similar nutritional status were matched with the noncancer group, increases in RBC putrescine level and putrescine-spermidine ratio were noted in the selected cancer patients. These results suggest that correction of nutritional deficits did not contribute significantly to the RBC polyamine pool and that increases in RBC polyamines during intravenous hyperalimentation were related to the presence of tumor.