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Summary(12). Both facts influence neonatal dosage because the newborn Rats 4 or 5 days old and 8 to 10 weeks OM were Injected Ip with 16 mg [14Clgentamicin sulfate/kg body weight and ktween 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 gen tamicin measured by 14C correlated well with the results ~Cradioimmunoassay. The extracdlular fluid space of neonatal and adult heart, muscle, kidney, lung, and liver was measured in vitro with ("Clcarboxyl inulia. Gentamicin disappeared from the adult circulation exponentially with a rate constant of 1.54% min-' but mare slowly from neonatal plasma. The semilogarithmic plot of neonatal plasma gen tamicin against time was curvilinear, suggesting that the drug was distributed in more than one M v comrrartment. The renal concentration of h i n t has poorer renal function, but a Lrger extracellular space than the adult. The former point led to infants receiving inappropriately low doses of the antibiotic until clinical trials (8-10) established the need for a higher dose, expressed as milligrams per kilogram body weight, in the baby than in the adult. In one of the above studies (81, measurements were made of tissue gentamicin concentrations in four infants who died. No1 only the kidney, but also the lung, liver, and heart were found to retain gentamicin after the drug had been cleared from the plasma. This observation led to speculation that, in the newborn at least, gentamicin might penetrate the intracellular compartment. The concept has been explord in the work reported here using [14C] gentamicin and the rat as an experimental model. gentamicin in the adult rai was four times greater than the peak plasma level at 0.5 hr and continued to rise thereafter to a
MATERIALS A N D METHODSmaximum of 240 n d m g at 4 hr, whkh was sustained at 8 hr-In Sprague-Dawley rats of both sexes and two age groups were the neonate a qualitatively similar result was obtained but the studied. The neonatal rats were 4 or 5 days old and weighed 6 to ~0IIcen'ItrfItioII~ were low&. In neonatal muscle the mean genta-9 g while the adults weighed 200 to 250 and were 8 to 10 weeks micin concentration was three times greater than that in the adult old. h c h animal was injected ip with a solution of ['4C~gentamicin at 0.5 h i and the difference between the two ages h a m e greater sulfate [specific activity, 0.83 pCi/mg (2 l)] dissolved in phosphateas time passed, rising to l@fold at 8 hr. The mean lung concentra-buffed saline (~~l b~~ A; oxoid ~t d . 1 at a concentration of tions in the adult and neonaw were similar at 0.5, 1, and 2 hr but 1-3 ,g/ml. The nominal dose was 16 mg gentamicin sulfate/kg a t 4 and 8 hr neonatal lung gentamicin levels were greater than body weight and the exact dose given was calculated by weighing those in the adult. Gentamicin was detectable in adult b r h at 0.5 the syringe before and after injection. ~1 1 calculations of plasma and 1 hr only...
