Role of humoral mediators in, and influence of a liposomal formulation on, acute amphotericin B nephrotoxicity.
The mechanisms responsible for amphotericin B nephrotoxicity remain incompletely understood, but clearly involve reduction in renal blood flow and glomerular filtration rate. Both direct effects of amphotericin B on contractile vascular cells, and indirect effects, due to humoural mediators, have been proposed. This study examines the role of nitric oxide, endothelin and angiotensin II in the acute nephrotoxic effects of amphotericin B in rats, and compares the anti-fungal and nephrotoxic effects of liposomal amphotericin B and amphotericin B-deoxycholate. Anaesthetized rats were given infusions of amphotericin B-deoxycholate in the presence or absence of N-nitro-L-arginine, PD 145065, a non-specific endothelin receptor antagonist, and L-158809, an angiotensin II type I receptor antagonist, or increasing doses of liposomal amphotericin B. Amphotericin B-deoxycholate (0.03 mg/kg/min intravenously) caused a significant 44% reduction in glomerular filtration rate and 65% maximal fall in renal blood flow. N-Nitro-L-arginine-treated rats had a lower renal blood flow and glomerular filtration rate at baseline, but sustained similar reduction of 53% and 75% in these parameters, respectively. PD145065 and L-158809 did not modify these effects either. Increasing doses of liposomal amphotericin B (from 0.01 up to 0.50 mg/kg/min.) induced no change in either glomerular filtration rate or renal blood flow. In vitro susceptibility tests revealed similar potency for liposomal amphotericin B and amphotericin B-deoxycholate in their fungistatic effects and slightly higher potency for amphotericin B-deoxycholate in their fungicidal effect. These results suggest that endogenous endothelin, angiotensin II or nitric oxide systems are not involved in the nephrotoxic effects of amphotericin B. The liposomal amphotericin B results suggest that amphotericin B nephrotoxicity is due to a direct interaction of amphotericin B with renal cells that is prevented by its encapsulation in liposomes.
Sabra
R
R
Department of Pharmacology and Therapeutics, Faculty of Medicine, American University of Beirut, Lebanon. rsabra@aub.edu.lb
Zeinoun
N
N
Sharaf
L H
LH
Ghali
R
R
Beshara
G
G
Serhal
H
H
D000666:Amphotericin B / Q000008:administration & dosage / Q000633:toxicity*; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000633:toxicity*; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000502:physiology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007674:Kidney Diseases / Q000139:chemically induced* / Q000503:physiopathology; D008081:Liposomes / Q000008:administration & dosage; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D009603:Nitroso Compounds / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology
D000935:Antifungal Agents; D004338:Drug Combinations; D016232:Endothelins; D007093:Imidazoles; D008081:Liposomes; D009603:Nitroso Compounds; D009842:Oligopeptides; D013777:Tetrazoles; D003840:Deoxycholic Acid; D000804:Angiotensin II; C084185:N-nitrosoarginine; C082887:PD 145065; D009569:Nitric Oxide; C070967:L 158809; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; D001120:Arginine