The pulmonary uptake of 1-alpha-acetylmethadol (LAAM) and methadone was studied during a single pass through the isolated perfused rat lung (IPL). The IPL was perfused for 10 min with perfusate containing various concentrations of one of the radiolabeled drugs, followed by a 30-min drug-free perfusion and the amount of radioactivity in the pulmonary venous effluent was used to estimate uptake and efflux of the drugs with time. Both drugs were extensively taken up by the IPL; however, LAAM uptake was significantly greater than that of methadone. The amount of each drug taken up was a nonlinear function of concentration in the perfusate, suggesting saturability of the major uptake processes. During drug-free perfusion LAAM and methadone previously accumulated were released from the lung at two different efflux rates; however, a third, more rapid efflux process for methadone was also evident. The total venous effluent collected during the drug-free perfusion contained a significantly greater fraction of the accumulated methadone as compared to LAAM. Calculation of the total amount of each drug effluxable at the observed rates indicated that another pool for both drugs existed in the lung that did not efflux at an observable rate. The accumulated LAAM remaining in this "slowly effluxable pool" was significantly greater than methadone. These data demonstrate a greater pulmonary uptake and tissue sequestration of LAAM as compared to methadone, and may be one of the contributing factors in the persistence of LAAM and its active metabolites in the body.