Tissue Gentamicin Concentrations in the Newborn and Adult rat

Abstract

Summary: Rats 4 or 5 days old and 8 to 10 weeks old were injected ip with 16 mg [¹⁴C]gentamicin sulfate/kg body weight and between 4 and 15 animals were killed at 0.5, 1, 2, 4, and 8 hr. Blood, liver, heart, kidneys, skeletal muscle, lung, and brain were collected and analyzed for radioactivity. Tissue gentamicin measured by ¹⁴C correlated well with the results of radioimmunoassay. The extracellular fluid space of neonatal and adult heart, muscle, kidney, lung, and liver was measured in vitro with [¹⁴C]carboxyl inulin. Gentamicin disappeared from the adult circulation exponentially with a rate constant of 1.54% min⁻¹ but more slowly from neonatal plasma. The semilogarithmic plot of neonatal plasma gentamicin against time was curvilinear, suggesting that the drug was distributed in more than one body compartment. The renal concentration of gentamicin in the adult rat was four times greater than the peak plasma level at 0.5 hr and continued to rise thereafter to a maximum of 240 ng/mg at 4 hr, which was sustained at 8 hr. In the neonate a qualitatively similar result was obtained but the concentrations were lower. In neonatal muscle the mean gentamicin concentration was three times greater than that in the adult at 0.5 hr and the difference between the two ages became greater as time passed, rising to 10-fold at 8 hr. The mean lung concentrations in the adult and neonate were similar at 0.5, 1, and 2 hr but at 4 and 8 hr neonatal lung gentamicin levels were greater than those in the adult. Gentamicin was detectable in adult brain at 0.5 and 1 hr only, values thereafter being insignificantly different from zero. In contrast, the mean brain gentamicin concentration of the neonates rose progressively to a peak of 1.26 ng/mg at 4 hr and had not fallen significantly at 8 hr. In all tissues the extracellular space was significantly greater in the neonate but the degree of difference varied markedly, it was greatest in the liver and least in the lung. The renal concentration of gentamicin in both the adult and neonate was always in excess of the plasma concentration. In the adult there was no evidence of intracellular gentamicin in heart or muscle, but the mean lung concentration exceeded that in the lung extracellular space by 0.9 to 3.0 ng/mg at all times studied, and the mean "intracellular" gentamicin concentration in liver was 0.5, 1.5, and 1.4 ng/mg at 2, 4, and 8 hr, respectively. In neonatal lung and muscle, intracellular gentamicin was detectable from 2 hr on and the concentration remained stable at 1.21 to 2.32 ng/mg. In liver intracellular gentamicin was first detected at 4 hr when the mean concentration was 1.6 ng/mg, but at 8 hr this had risen to 3.71 ng/mg. Cardiac intracellular gentamicin was present at 8 hr in a low but significant concentration of 0.59 ng/mg.

Speculation: In the neonatal rat gentamicin penetrates the intracellular compartment and traverses the blood-brain barrier. The pharmacology of aminoglycoside antibiotics may be influenced by immaturity in other species also.

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