ACCUMULATION DES AMINOSIDES DANS LES TISSUS. ETUDE COMPARATIVE DE LA GENTAMICINE ET DE LA TOBRAMYCINE CHEZ DES MALADES AUX REINS SAINS

Forty-seven patients receiving gentamicin (G) and 20 patients receiving tobramycin (T) were studied during treatment of serious infections. The patients had varied creatinin clearances (CCr), with dosage alteration made in cases of impaired renal function. Similar ages, underlying disease states, infection sites, concurrent therapy, mean total dosage, serum concentrations were measured by both microbiological and radioimmunoassay (RIA) methods, with good agreement. Use of RIA with its lower limit of sensitivity (0.03 μg/ml) revealed that, following the final dose of G or T, serum concentrations decline in two phases, with concentrations measurable for 10 days in all patients, and a second phase half-life of over 100 hours for both G and T. The first phase half-life is dependent on renal function as noted in previous studies and ranged from 2 to 45 hours. The significance of the prolonged detection of G and T was assessed using a two-compartment model. The model parameters were obtained from non linear least-squares regression analysis of the biphasic decline in serum concentration after the final dose of G or T. These parameters were employed in a stimulation program to predict serum concentrations and to calculate the amount in the tissue compartment throughout therapy. For each patient studied, measured and predicted serum concentrations were in close agreement. Several patients in both groups expired and their postmortem tissue concentrations were used to confirm the two-compartment model. Analysis of tissue concentrations revealed uneven distribution of G and T among various body tissues, with both antibiotics concentrated in the kidney cortex. We conclude that tissue persistence and prolonged washout of G and T in man is well described by a two-compartment pharmacokinetic model, and that accumulation of aminoglycosides in kidney tissue may contribute to their nephrotoxicity.