Kinetics of gentamicin (2.2 mg/kg of body weight) were investigated in 7 sheep after IV bolus administration. The mean serum concentration profile could be described by a 2-compartment open model with a distribution rate constant (alpha) of 3.112 +/- 1.681 hour-1 [half-life, t1/2(alpha) = 17.22 +/- 8.63 minutes] and an overall elimination rate constant (beta) of 0.485 +/- 0.028 hour-1 [t1/2(beta) - 85.87 +/- 5.03 minutes]. The apparent volume of distribution was somewhat restricted [Vd(area) = 0.194 +/- 0.059 L/Kg], and the total body clearance was 1.559 +/- 0.400 ml/kg/min. Equal dosages of gentamicin (2.2 mg/kg) were also given IM and intratracheally (IT). after IM injection, gentamicin reached peak serum concentration at postinjection minutes (PIM) 45, surpassing concentrations after the IV injection for the remainder of the experiment. The IT injection produced detectable serum concentrations at PIM 5, with a peak concentration at PIM 60. The serum drug concentrations after IT injections remained well below concentrations after IV and IM injections. Radiographic analysis of an IT injection of a gentamicin-tantalum suspension revealed good distribution throughout the trachea and proximal bronchi, with physical clearance of the tantalum occurring after greater than or equal to 10 minutes. Aspiration biopsy of the tracheal wash 6 hours after IT gentamicin injection revealed no cytologic response to gentamicin in 6 of 7 sheep, with the single response that of a purulent exudate.