The pulmonary uptake of l-alpha-acetylmethadol (LAAM) and its major analgesically active metabolites, nor-LAAM and dinor-LAAM, was studied during a single pass through the isolated perfused rat lung (IPL). The radiolabeled drugs were infused into the IPL for 10 min followed by a 30-min drug-free perfusion. All three drugs were extensively taken up into the IPL; however, dinor-LAAM, the least lipophilic, accumulated to the greatest extent. Their rates of efflux from the IPL with time could be described by the sum of three exponentials and 20-25% of each compound accumulated in a "slowly effluxable pool," suggesting a highly sequestered pool of drug in the lung. These findings suggest that tissue sequestration of the active metabolites is equal to or greater than LAAM itself. Such tissue sequestration could limit the sequential metabolic activation or inactivation, and serve as a reservoir of the active compounds. These factors favor the persistence of LAAM and its active metabolites in the body, thus prolonging the opiate-like effects after LAAM administration. The data also indicated that the relationship between drug basicity or lipophilicity and extent of uptake is complex and it is difficult to associate a particular physicochemical property with the extent or character of pulmonary drug uptake.