Toxicity and Tissue Distribution of Aminophylline in Neonatal and Adult Mice and Rats

Abstract

Summary: The LD₅₀ of aminophylline in adult mice differed from young mice and rats of both ages, in which the values were remarkably similar (Table 1). With the exception of fat, which had lower concentrations in all groups, tissue concentrations after a 4 mg/kg rectal dose of aminophylline in the 10-day-old animals ranged from 10–20 μg/g as compared to 4–10 μg/g in the adults (Table 2). To evaluate preferential distribution, an analysis of tissue to blood concentration ratios was made. All ratios approximated 1.0 except fat which had a ratio of 0.1–0.6. The neonates of each species had significantly higher tissue to blood ratios for brain, heart, small intestine, skeletal muscle, and fat (P < 0.05). Brain to plasma and brain to blood ratios were very similar ranging from 0.4–1.3 in adults versus 0.8–1.7 in neonates. Consideration of the time course indicated a trend toward unit, with the overall ratio in both groups being 1.15 at 2 hr. However, at all earlier time periods the ratios were clearly higher in neonates. Administration of aminophylline intraperitoneally to produce serum concentrations of tneophylline far in excess of the 10–20 μg/ml considered to be safe and effective in clinical use did not decrease bilirubin levels in young or old Gunn rats (Fig. 1).

Speculation: The similarities of LD₅₀ and tissue distribution between neonatal and adult rodents suggests that studies of metabolism may prove to be most important in explaining differences in serum elimination times noted in prematures treated with aminophylline.

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