Contribution of lungs to total body clearance: linear and nonlinear effects

The contribution of the lungs to the total body clearance of drugs is examined in a framework that emphasizes their anatomical position. For intravenous administration, the lung is the only organ other than blood that can account for a total body clearance in excess of the cardiac output. Systemic arterial drug concentration and tissue drug exposure are inversely proportional to total body clearance. Although the role of the lung has been overshadowed by that of the liver, several examples are presented to demonstrate that relatively small amount of pulmonary activity can produce a large reduction in systemic arterial drug concentration. For oral administration, first-pass elimination by the liver and lungs in series results in a synergistic increase in total body clearance. Nonlinear effects caused by saturation of elimination pathways are also examined. Increased emphasis on experimental investigation of the pulmonary contribution is warranted, especially for drugs with high apparent clearance.