Pharmacokinetic profile of ABELCET (amphotericin B lipid complex injection): combined experience from phase I and phase II studies.

Amphotericin B (AmB) has been the most effective systemic antifungal agent, but its use is limited by the dose-limiting toxicity of the conventional micellar dispersion formulation (Fungizone). New formulations with better and improved safety profiles are being developed and include ABELCET (formerly ABLC), but their dispositions have not been well characterized; hence, the reason for their improved profiles remains unclear. This report details the pharmacokinetics of ABELCET examined in various pharmacokinetic and efficacy studies by using whole-blood measurements of AmB concentration performed by high-pressure liquid chromatography. The data indicated that the disposition of AmB after administration of ABELCET is different from that after administration of Fungizone, with a faster clearance and a larger volume of distribution. It exhibits complex and nonlinear pharmacokinetics with wide interindividual variability, extensive distribution, and low clearance. The pharmacokinetics were unusual. Clearance and volume of distribution were increased with dose, peak and trough concentrations after multiple dosings increased less than proportionately with dose, steady state appeared to have been attained in 2 to 3 days, despite an estimated half-life of up to 5 days, and there was no evidence of significant accumulation in the blood. The data are internally consistent, even though they were gathered under different conditions and circumstances. The pharmacokinetics of ABELCET suggest that lower concentrations in blood due to higher clearance and greater distribution may be responsible for its improved toxicity profile compared to those of conventional formulations.

Amphotericin B protects cis-parinaric acid against peroxyl radical-induced oxidation: amphotericin B as an antioxidant.

The antifungal effects of amphotericin B are believed to be due to two possibly interrelated mechanisms: an increase in permeation by binding to sterols in cellular membranes and a prooxidant effect causing oxidative damage in target cells. However, the seven conjugated double bonds in amphotericin B raise the possibility that it could be highly susceptible to autoxidation, causing an antioxidant effect. In the present study, we investigated the prooxidant and antioxidant properties of amphotericin B in a model system in which oxidation of a reporter molecule, cis-parinaric acid, was induced by azo initiators of peroxyl radicals. Since interactions of amphotericin B with sterols are essential for its pharmacological and toxic actions, we also studied the effects of cholesterol on the prooxidant and antioxidant properties of amphotericin B. Amphotericin B caused a noncollisional quenching of a characteristic fluorescence of cholesteryl cis-parinarate integrated in liposomes, suggesting the formation of amphotericin B-cholesteryl cis-parinarate complex. This effect of amphotericin B was ablated by increasing concentrations of cholesterol. We found that amphotericin B inhibited oxidation of cis-parinaric acid complexed with human serum albumin [using a water-soluble azo initiator, 2,2'-azobis(2aminopropane)dihydrochloride] and in liposomes [using a lipid-soluble azo initiator, 2,2'-azobis(2,4-dimethylvaleronitrile)]. The inhibitory effect of amphotericin B on 2,2'-azobis(2,4-dimethylvaleronitrile)-induced peroxidation of cis-parinaric acid in liposomes was also diminished by cholesterol. The antioxidant effect of amphotericin B in this model system suggests that amphotericin B does not exert its pharmacological and toxicological responses through a prooxidant effect to cause damage in target cells.

Reduced liver function is the trigger for renal sodium retention following portal vein ligation in the rat.

Sodium retention along with peripheral vasodilation are features of prehepatic portal hypertension. In several models of experimental liver damage, sodium retention occurs only when hepatic function, measured by the aminopyrine breath test (ABT-k), falls below a critical threshold. The relationship between renal sodium handling, ABT-k and systemic and renal haemodynamics in partial portal vein ligated (PVL) rats was examined to test hypothesis that peripheral vasodilation was responsible for initiating sodium retention. Haemodynamic measurements were conducted early after surgery in portal hypertensive rats with and without sodium retention and in sham-operated controls. Compared with control, both PVL groups of rats had elevated portal pressure and lower peripheral vascular resistance (P < 0.05). Sodium retaining-PVL rats had both lower ABT-k (0.95 +/- 0.05 vs 1.38 +/- 0.06 x 10(-2)/min; P < 0.05) and higher sodium balance (1.38 +/- 0.09 vs 0.43 +/- 0.09 mmol/day; P < 0.05) than non-sodium retaining PVL rats. No differences in plasma renin activity or noradrenaline concentrations were observed. In a separate group of rats, hydralazine-induced pheripheral vasodilation did not induce sodium retention. These results suggest that the presence of peripheral vasodilation alone is not sufficient to trigger a sodium-retaining status. A factor, probably liver function-dependent, acting directly on renal tubules may be necessary for changes in renal sodium handling in this model.

Adenosine does not mediate renal sodium retention and peripheral vasodilation elicited by partial portal vein ligation in rats.

This study was conducted to assess the role of adenosine in the peripheral vasodilation and sodium retention that occurs after partial portal vein ligation (PVL) in the rat. The experiment was performed on day 1 after surgery when transient maximal sodium retention developed and day 7 when rats returned to sodium balance. Hemodynamic studies were conducted under anesthesia in portal hypertensive rats with sodium retention and in sham-operated controls. Measurements were obtained before and after administration of a nonselective A1 and A2 adenosine receptor antagonist 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX) (10 mg/kg intravenously followed by 150 micrograms/min). Under baseline conditions, portal hypertensive rats with sodium retention were hypotensive, with decreases in total peripheral resistance and filtration fraction on day 1 in comparison with the control group. Although hyperdynamic circulation was still maintained by day 7, there was a return to sodium balance. The adenosine receptor antagonist had a modest vasoconstrictor effect on systemic and renal vasculature in both groups, but less in portal hypertensive rats. However, no change in glomerular filtration rate was observed. DPSPX induced a natriuresis in control rats (from 0.40 +/- 0.11 to 5.97 +/- 0.61 mEq/min on day 1, from 0.48 +/- 0.20 to 6.34 +/- 0.45 mEq/min on day 7). This response was attenuated in portal hypertensive rats on day 1 (from 0.14 +/- 0.04 to 1.67 +/- 0.57 mEq/min). but not on day 7 (from 0.20 +/- 0.06 to 5.11 +/- 0.55 mEq/min). These results suggest that in portal hypertensive rats (1) adenosine is not responsible for vasodilation and sodium retention, (2) a sodium-retaining factor acting directly on the renal tubule is responsible for sodium retention.

An automated and portable low-flow pulsatile perfusion system for organ preservation.

While machine preservation reduces the incidence of delayed graft function in renal transplant recipients, it is only used in 10% of kidney transplantations. The performance of our portable, low-flow-pulsatile organ perfusion system was examined in a canine kidney autotransplantation model. Grafts were stored for 72 h by simple cold preservation in University of Wisconsin (UW) solution, or by high or low-flow machine preservation After preservation, the grafts were autotransplanted and the animals were followed for 15 days. Graft function was better in machine-preserved kidneys. Tissue biochemistry indicated that machine preservation resulted in higher levels of adenine nucleotides and better histological integrity than the cold storage. While histology and biochemistry of machine-preserved groups were similar, electromicroscopy of high-flow grafts showed mild accumulation of intravenous debris and endothelial swelling. This study shows that a simplified machine perfusion technique is effective for organ preservation.

Nitric oxide does not contribute to sodium retention and peripheral vasodilation induced by partial portal vein ligation in rats.

The role of nitric oxide (NO) synthesis in the peripheral vasodilation and sodium retention that occurs after partial portal vein ligation (PVL) was investigated. Hemodynamic studies in PVL rats with sodium retention and in sham-operated controls were conducted on the day when PVL rats developed transient and maximal sodium retention. Measurements were obtained before and during two consecutive periods after NO synthesis inhibition with NG-monomethyl-L-arginine (L-NMMA). Under baseline conditions, PVL rats with sodium retention were hypotensive, with equivalent decreases in total peripheral resistance and glomerular filtration rate in comparison to the control group. After L-NMMA, peripheral resistance and arterial pressure increased by similar extent in both groups. As compared with controls, PVL rats with sodium retention remained hypotensive and vasodilated. Furthermore, L-NMMA-induced natriuresis was attenuated in the PVL group. Additionally, serum and urinary levels of nitrate and nitrite did not vary before surgery and at the time of sodium retention. These results suggest that in PVL rats (1) vasodilation is not NO mediated; (2) vasodilation is not a sufficient explanation for sodium retention, and (3) a sodium-retaining factor acting on the renal tubules is responsible for sodium retention.

Potassium depletion potentiates amphotericin-B-induced toxicity to renal tubules.

Hypokalemia and potassium depletion are frequent complications of amphotericin B therapy. Both ischemic and gentamicin-induced renal failure is potentiated by potassium depletion; it is, therefore, possible that amphotericin B nephrotoxicity is similarly influenced. This study evaluated whether the acute nephrotoxic response to amphotericin B is potassium sensitive. Potassium-depleted and control rats were subjected to an acute intravenous infusion of either amphotericin B (AmB-K; AmB, n = 10 in each) or its vehicle (V-K, V; n = 6 in each). Potassium-depleted rats had both lower urinary daily excretion and lower plasma levels of potassium than control animals (0.1 +/- 0.0 vs. 2.1 +/- 0.2 mEq/day, p < 0.001, and 3.8 +/- 0.2 vs. 1.9 +/- 0.1 mEq/l, p < 0.001, respectively). In AmB and AmB-K groups, there were equivalent falls in glomerular filtration rate and renal blood flow, and a rise in renal vascular resistance, compared with V and V-K. In contrast, the AmB-K group showed a higher urinary excretion of sodium (AmB-K vs. AmB: 2.9 +/- 0.7 vs. 1.1 +/- 0.3 microEq/min; p < 0.05) and fractional excretion of Na (AmB-K vs. AmB: 1.6 +/- 0.4 vs. 0.6 +/- 0.1%; p < 0.05) in comparison to the AmB group. Neither of these parameters changed in either amphotericin B or vehicle-treated groups. These results suggest that potassium depletion does not influence the acute renovascular effects of amphotericin B but potentiates its tubular toxicity. This may have clinical implications since hypokalemia and potassium depletion are frequent complications of amphotericin B therapy.