Attenuation of amphotericin B nephrotoxicity in the dog by the fenoldopam prodrug, SK&F R-105058.

Amphotericin B administration to 8 dogs (1 mg/kg.d, i.v.) for 3 days resulted in significant (P less than .01) reductions in 24-hr creatinine clearance. SK&F R-105058 is an N-ethyl carbamate ester prodrug of the selective DA1 receptor agonist, fenoldopam, which, on oral administration to dogs, results in sustained plasma levels of the renal vasodilator, fenoldopam. Treatment of 6 dogs with SK&F R-105058 (10 mg/kg p.o. b.i.d.) resulted in a significant attenuation of the amphotericin B-induced reductions in creatinine clearance observed on days 2 and 3 after initiation of amphotericin treatment. However, the increase in urine flow and fractional sodium excretion induced by amphotericin B was not altered by SK&F R-105058 treatment. Subsequent histological analysis of the kidneys demonstrated lesions consisting of multifocal tubular degeneration, necrosis and mineralization of mostly distal tubules. Quantitation of tubular lesions indicated that SK&F R-105058 significantly reduced the morphological changes induced by amphotericin B. The data indicate that administration of a fenoldopam prodrug can delay amphotericin B-induced reductions in glomerular filtration rate in the dog.