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.
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
D P
DP
Brooks
M P
MP
Mitchell
B G
BG
Short
R R
RR
Ruffolo
A J
AJ
Nichols
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000666:Amphotericin B / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D003404:Creatinine / Q000378:metabolism; D004231:Diuresis / Q000187:drug effects; D004285:Dogs; D018818:Fenoldopam; D007668:Kidney / Q000187:drug effects*; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D011355:Prodrugs / Q000494:pharmacology*
D001552:Benzazepines; D002219:Carbamates; D011355:Prodrugs; C068716:SK&F R-105058; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000666:Amphotericin B; D003404:Creatinine; D018818:Fenoldopam