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1 Two methods of pethidine administration, namely constant-rate infusion and single i.v. injection, were used to assess the pulmonary disposition of the drug in 10 postoperative patients. Using two sites of blood sampling, the pulmonary extraction ratio was determined. 2 Pronounced pulmonary uptake of pethidine was found in all patients (n = 10). On the other hand, there was no significant evidence of pulmonary clearance. 3 The mean total plasma clearance was 810 ml min-' and the volume of distribution was 3.1 1 kg-1. 4 A flow model was used to describe the disposition of pethidine in man. The concentration-time profiles calculated by the model were in accordance with observed data. The data showed that both pulmonary uptake and pulmonary release of pethidine were rapid. 5 Constant-rate infusion was found advantageous in the determination of pulmonary extraction, with respect to the accuracy and precision of the results. The extraction obtained after a single injection may be overestimated on account of uptake of the drug by the lungs.

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The influence of lung uptake and lung clearance on the disposition of morphine was studied in surgical patients. In the postoperative period morphine was given intravenously by a two-rate infusion regimen. Under steady-state conditions samples of mixed central venous blood (pulmonary artery) and peripheral arterial blood (radial artery) were taken simultaneously and at the same time cardiac output was measured. The concentration differences between venous and arterial blood were used to calculate the extraction ratio of morphine across the lung. In all patients there was marked pulmonary uptake, but the concentration differences in most of them were small under steady-state conditions. The extraction ratio (mean +/- SD) across the lung was 0.06 +/- 0.10, implying insignificant lung clearance. However, in two patients, both with diabetes mellitus, there was a significant concentration gradient, indicating that the lung could contribute to the total body elimination of morphine. On the other hand, the total clearance was similar in diabetic and nondiabetic patients (1190 and 1150 ml/min, respectively), implying that pulmonary clearance would have no significant influence on the kinetics of morphine. A physiologically based pharmacokinetic model was used to describe the disposition of morphine in post-operative patients. The model allowed simulation of pulmonary diffusion, uptake and elimination and supported conclusions based on model-independent experimental data.