Concentrations in serum and distribution in tissue of free and liposomal amphotericin B in rats during continuous intralipid infusion

Abstract

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).

Safety, Tolerance, and Pharmacokinetics of High-Dose Liposomal Amphotericin B (AmBisome) in Patients Infected withAspergillusSpecies and Other Filamentous Fungi: Maximum Tolerated Dose Study

“…This preservation of glomerular function by lipid formulations of amphotericin B is related to several possible mechanisms. Lipid formulations of amphotericin B have a high affinity for binding to high-density lipoproteins (HDL) (46)(47)(48)(49). Binding to HDL promotes uptake in the reticuloendothelial system (RES), which has a relatively high level of expression of HDL receptors.…”

Heat Treatment of Amphotericin B Modifies Its Serum Pharmacokinetics, Tissue Distribution, and Renal Toxicity following Administration of a Single Intravenous Dose to Rabbits

“…dose of FZ (n ϭ 6) or HFZ (n ϭ 4) (1 mg of AmpB/kg) through the jugular vein. Preliminary studies have shown that an FZ dose of 1 mg/kg is sufficient to treat experimental candidiasis and yet exhibits measurable kidney toxicity (16)(17)(18)(19)(20). Following FZ and HFZ administration serial blood samples were obtained and stored in centrifuge tubes prior to and 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, 24, and 48 h after the injection.…”

“…Serum and tissue samples were obtained and processed for AmpB analysis as previously described (16,(18)(19)(20). AmpB levels in serum and tissues were determined by high-pressure liquid chromatography using an external calibration curve as previously described (16,(18)(19)(20).…”

“…The conventional AmpB-deoxycholate micellar formulation, Fungizone (FZ) (Bristol-Myers Squibb, Princeton, N.J.), has been used for over 45 years, and, despite its dose-dependent kidney toxicity, it remains the most widely used drug for the treatment of most systemic fungal infections (2,8,13). In addition, lesstoxic liposomal and lipid-associated AmpB formulations have been developed (e.g., AmBisome, Abelcet, and Amphocil), and, although they have been proven to reduce AmpB-induced kidney toxicity (6,(16)(17)(18)(19)(20), their use has been limited by their high expense.…”

Role of plasma lipoproteins in modifying the toxic effects of water-insoluble drugs: Studies with cyclosporine A

“…These findings suggest that CSA lipoprotein distribution may be partially regulated by plasma lipoprotein cholesterol and to a lesser extent triglyceride concentrations. It further suggests that the redistribution of drug from one lipoprotein class (HDL) to another (LDL or VLDL) could be influenced by different disease states and adjunct therapies such as intralipid infusion, in which lipoprotein plasma concentrations and composition are altered 25 .…”