Steady-state determination of the contribution of lung metabolism to the total body clearance of drugs: application to carbamazepine.

A steady-state approach is proposed to examine the contribution that the lung makes to the total body elimination of medium- to high-clearance drugs. Carbamazepine, a potential candidate of pulmonary metabolism, was investigated by infusion into the femoral vein in seven unrestrained Sprague-Dawley rats (250-300 g). Blood samples (0.45 ml), taken simultaneously from the jugular vein and carotid artery in each rat during the infusion (2-5 days), were assayed in duplicate for carbamazepine by GLC/CI/MS. Venous blood concentrations were used to calculate the total body clearance of carbamazepine, 440 +/- 38 ml/hr (mean +/- SEM), and the difference between simultaneous venous and arterial blood concentrations were used to calculate the extraction ratio of carbamazepine by the lung. The mean extraction ratio of 0.0058 (n = 28) suggests that the lung only contributes approximately 5% to the total body clearance of carbamazepine. It is proposed that this technique could be useful in examining the importance of the lung in the total body clearance of other drugs, and that it has several advantages over some currently used techniques.