UPTAKE, METABOLISM AND EFFLUX OF METHADONE IN SINGLE-PASS ISOLATED PERFUSED RABBIT LUNGS

  • 1 January 1976
    • journal article
    • research article
    • Vol. 199  (2) , 360-367
Abstract
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 2 uptake processes (I1 and I2). 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 3 rates (T1/2 [half life] = 0.37, 1.65 and 8.9 min) suggesting that accumulated methadone was stored in at least 3 pools (E1, E2, and E3). A pool with a half-life in excess of 5 h (noneffluxable pool) was also detected; this noneffluxable pool was not 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. The decrease in the rate of efflux of the metabolites with respect to time was identical to that of unchanged methadone.