Kinetic aspects of drug disposition in the lungs

1. The pharmacokinetic role of the lungs has been extensively studied using in vitro preparations, but this information has not been well integrated into many systemic pharmacokinetic models. 2. The lung is characterized by short diffusion distances, extremely high relative perfusion and heterogeneous cell types. Anionic and neutral lipophilic drugs have relatively small distribution volumes in the lungs due to their low lipid content. Cationic lipophilic drugs can accumulate in the lungs, probably due to trapping in mitochondria and lysosomes, forming very slowly eluting pools. 3. Drug metabolism in the lungs is possible, but not universal. The lung, generally, has a low activity for many of the metabolic enzymes found in the liver, although this activity is relatively more inducible. The resultant drug extraction would be 'enzyme limited', variable and flow dependent. 4. Double indicator studies of first-pass lung kinetics can characterize short-term distribution in the lungs, but not longer-term distribution or metabolism; the converse applies for studies of drug concentration gradients across the lungs. No single study or model has adequately defined the short- and long-term kinetics of drugs in the lungs. 5. Drug clearance in the lungs can contribute to an apparent total body clearance in excess of hepatic blood flow and cardiac output. The lung is a first pass filter for any drug administered on the venous side of the circulation and can act as a 'capacitor' that damps the first-pass concentration peak in the blood after intravenous bolus injection.