Uptake, metabolism and efflux of methadone in "single pass" isolated perfused rabbit lungs

The uptake, metabolism and persistence of racemic, d- and l-methadone were studied in the isolated perfused rabbit lung. The removal of the drug from the perfusate was resolved into two uptake processes (I1 and I2Y. The unidirectional flux of methadone from the perfusate into the lung was linear with respect to perfusate concentration, suggesting an uptake mechanism involving diffusion and/or binding. The uptake of d- and l-methadone was identical. In the absence of methadone in the perfusate, methadone that previously had accumulated in the lung effluxed at three rates (T1/2 = 0.37, 1.65 and 8.9 minutes) suggesting that accumulated methadone was stored in at least three pools (E1, E2, and E3) In addition, a pool with a half-life in excess of 5 hours (noneffuxable pool) was detected; this noneffluxable pool was shown not to be the result of irreversible covalent binding. Methadone was biotransformed to a small extent by the isolated perfused lung to mono- and di-N-demethylated metabolites. Although unchanged methadone and its N-demethylated metabolites were consistently found in the lung at the end of efflux, the mono-N-demethylated metabolite was not always detectable in the perfusate. Nevertheless, the decrease in the rate of efflux of the metabolites with respect to time was identical to that of unchanged methadone.