Pulmonary clearance of vasoactive drugs: N-oxidation of SK&F 86466 in the isolated perfused rat lung

The contribution of the lung to the systemic clearance of the alpha receptor antagonist SK&F 86466 in rats was determined using the isolated perfused rat lung. Lungs were perfused with a blood-free medium containing SK&F 86466 at initial concentrations ranging from 0.26 to 5.1 microM at a flow rate of 104 ml/min. During the perfusion the concentration of SK&F 86466 in the perfusion medium declined monoexponentially. The half-life (8.0 +/- 1.8 min), steady state volume of distribution (205 +/- 16 ml), clearance (18.3 +/- 2.4 mL/min) and extraction ratio (0.18 +/- 0.02) were independent of the initial concentration of SK&F 86466. The free fraction of SK&F 86466 in the perfusion medium, determined by equilibrium dialysis, was 0.598. The average intrinsic clearance of SK&F 86466 in the lung, calculated using the flow rate, free fraction and clearance, was 37.4 ml/min. The concentration of the N-oxide metabolite of SK&F 86466 (SK&F 102102) in the perfusion medium increased with time, and at the end of the perfusion was approximately equal to the initial concentration of SK&F 86466. The pharmacokinetics of SK&F 86488 in lungs from rats pretreated with the suicide substrate inhibitor of cytochrome P-450 1-aminobenzotriazole were identical to the kinetics in lungs from control animals. The pretreatment regimen used reduced the activity of ethoxycoumarin-O-deethylase in lung microsomes by 70% and reduced P-450 content to below the limit of detection.(ABSTRACT TRUNCATED AT 250 WORDS)