Attenuation of amphotericin B nephrotoxicity in the dog by the fenoldopam prodrug, SK&F R-105058 | Health & Environmental Research Online (HERO)

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Citation
Tags

HERO ID

7429471

Reference Type

Journal Article

Title

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

Author(s)

Brooks, DP; Mitchell, MP; Short, BG; Ruffolo, RR; Nichols, AJ; ,

Year

1991

Is Peer Reviewed?

Yes

Journal

Journal of Pharmacology and Experimental Therapeutics
ISSN: 0022-3565
EISSN: 1521-0103

Volume

257

Issue

Page Numbers

1243-1247

Language

English

PMID

1675291

Web of Science Id

WOS:A1991FQ59300045

Abstract

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.

Keywords

amphotericin b; dopamine 1 receptor; dopamine 1 receptor stimulating agent; fenoldopam 4',7,8 tris(n ethylcarbamate); prodrug; animal experiment; article; controlled study; creatinine clearance; diuresis; dog; drug inhibition; histology; intravenous drug administration; male; natriuresis; nephrotoxicity; nonhuman; oral drug administration; priority journal; Amphotericin B; Animal; Benzazepines; Carbamates; Creatinine; Diuresis; Dogs; Fenoldopam; Kidney; Kidney Tubules; Male; Natriuresis; Prodrugs; SK&F-38393