Comparative pharmacokinetics and safety of a novel lyophilized amphotericin B lecithin-based oil-water microemulsion and amphotericin B deoxycholate in animal models.
Amphotericin B (AmB) has been a most effective systemic antifungal agent, but its use is circumscribed by the dose-limiting toxicity of the conventional micellar dispersion formulation Fungizone (D-AmB). To lower AmB-associated toxicity, AmB may be integrated into oil-in-water lecithin-based microemulsions. The present study compares the pharmacokinetic characteristics of D-AmB with the alternative formulation of AmB in microemulsion (M-AmB), which has proved effective in a murine candidiasis model. Both formulations were given by intravenous bolus: D-AmB 1 mg/kg, and M-AmB 0.5, 1 or 2 mg/kg. The pharmacokinetics of D-AmB and M-AmB have several differences, specifically with regard to the respective Cmax and AUC0- infinity values. Elimination of AmB from serum was biphasic for both M-AmB and D-AmB. Single-dose D-AmB (1 mg/kg) achieved a Cmax of 3.89 +/- 0.48 mg/L and an AUC0- infinity of 32.28 +/- 7.31 mg.h/L, whereas single-dose M-AmB (1 mg/kg) by comparison achieved a lower Cmax (2.92 +/- 0.54 mg/L) and a lower AUC0- infinity (21.89 +/- 5.17 mg.h/L). To evaluate the safety of M-AmB, a multiple-dose toxicity study was performed in groups of 10 mice, each receiving D-AmB 1 mg/kg, or M-AmB 1, 1.5, 2 or 3 mg/kg. The findings suggest that, in comparison with D-AmB, M-AmB produces no histologically demonstrable renal lesions, or changes in clinical chemistry.
Brime
Begona
B
Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Complutense University of Madrid, Spain. begonab@farm.ucm.es
Frutos
Paloma
P
Bringas
Pilar
P
Nieto
Ana
A
Ballesteros
M Paloma
MP
Frutos
Gloria
G
D000666:Amphotericin B / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D019540:Area Under Curve; D003404:Creatinine / Q000097:blood; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000633:toxicity*; D004338:Drug Combinations; D004655:Emulsions; D005612:Freeze Drying; D006454:Hemoglobins / Q000378:metabolism; D007275:Injections, Intravenous; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D009821:Oils; D011817:Rabbits; D014867:Water
D004338:Drug Combinations; D004655:Emulsions; D006454:Hemoglobins; D009821:Oils; D003840:Deoxycholic Acid; D014867:Water; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; D003404:Creatinine