Tobramycin Disposition in the Rat Lung Following Airway Administration

Abstract

A realistic ex vivo model, the isolated perfused rat lung (IPRL), was used to investigate tobramycin's pulmonary disposition at typical therapeutic concentrations. Different nominal doses were administered in aqueous solution to the airways alongside nonbinding absorption markers, fluorescein and mannitol. The mean fraction of each administered dose reaching the perfusate (Fp) was determined as a function of time following administration. Dynamic dialysis was also used to quantify the kinetics of tobramycin binding and/or tissue retention in the IPRL immediately after drug administration. Whereas the absorption markers fluorescein and mannitol both showed monoexponential dose-independent increases in Fp with time, tobramycin's pulmonary absorption into the perfusate was biexponential and dose-dependent due to tissue binding or retention. Best estimates for the first-order rate constants of tobramycin absorption appeared dose-independent (0.065-0.070 min(-1)), with values close to the mean for fluorescein (0.076 min(-1)). The rate constant for dissociation from IPRL tissue was also relatively constant (0.018-0.022 min(-1)), whereas that for association decreased from 0.16 to 0.07 min(-1) with increasing airway dose from 0.002 to 2 mg. Dynamic dialysis data from sliced IPRL tissue following identical airway administration were consistent with those from the intact IPRL, confirming tobramycin's "slow on, slow off" binding and sequestration by the rat lung. Overall, tobramycin absorption was fast following airway administration. However, dose- and concentration-dependent slow-onset tissue binding extended the duration of tobramycin's presence in the rat lung. These findings may explain, in part, the apparent success of inhaled tobramycin therapy when treating pulmonary infections.