Abstract
The ferrocene hematinic MDL 80,478 was administered orally at dosages ranging from 0 to 500 mg/kg/day to dogs (2 weeks), monkeys (6 weeks), and rats (6 weeks). Rats given 500 mg/kg/day had distended abdomens due to enlarged livers while the high-dose (250 mg/kg/day) dogs and monkeys demonstrated the following signs: emesis, depression, ataxia, anorexia and a high number of deaths. Increase in serum total bilirubin, alkaline phosphatase, and glutamicpyruvic transaminase, indicators of hepatocellular injury, were detected in these high-dose dogs and monkeys prior to their deaths. Necropsy examination revealed yellowish discoloration of the abdominal fat of the rat and enlarged yellow livers of all three species. In the rat, increasing the dose of 25 to 250 mg/kg/day resulted in significantly (P < 0.05) elevated levels of plasma MDL 80,478 following long-term administration. At the highest dosage for each test animal drug-related microscopic lesions occurred in the livers as diffuse, Prussian blue positive, brown pigmentation (rats), fatty degeneration (dogs), and centrolobular necrosis (monkeys) and the adrenals with focal to diffuse cortical vacuolar degeneration (all three species). Ultrastructural evaluation of rat tissue demonstrated iron storage and hypertrophy of smooth endoplasmic reticulum (SER) of the liver and mild vacuolar degeneration of the mitochondria and lipid droplet accumulation of the adrenal cortex. In addition to increased SER, the parent compound caused in the liver of the rat increased hepatic activity of ethylmorphine N-demethylase and aniline hydroxylase with no change in cytochrome P-450 or microsomal protein, findings suggestive of mild drug-related induction of the monoxygenase system.
Published Version
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