CHARACTERIZATION OF (±)‐METHADONE UPTAKE BY RAT LUNG

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Abstract
1 By use of a sensitive and specific fluorescence assay procedure it was shown that after subcutaneous administration to rats, (±)-methadone was concentrated in the lung. Lung to serum ratios ranging from 25 to 60 were obtained indicating that the rat lung tissue was capable of extracting (±)-methadone against a concentration gradient. 2 This phenomenon was investigated in vitro with rat lung slices incubated in Krebs-Ringer phosphate buffer (pH 7.4). The uptake was expressed in terms of tissue to medium concentration ratios (T/M ratio). 3 The principal observations were: (i) Studies on the time-course of the uptake showed that the T/M ratios of (±)-methadone increased rapidly during the first 60 min of incubation and then more slowly, with a plateau occurring at 180 min; (ii) The T/M ratio of (±)-methadone progressively increased from 9.5 to 17 as the pH of the incubation medium was varied from 6.2 to 7.8; (iii) When the concentration of (±)-methadone in the incubation medium was varied from 0.005 to 0.5 mM, the T/M ratio decreased rapidly suggesting self-saturation of the transport process. Beyond the medium concentration of 0.5 mM, the T/M ratio declined very slowly. 4 These results suggested that at low concentrations, (±)-methadone was transported predominantly by a self-saturable process while at higher concentrations it was transported by a process of simple diffusion. 5 At low concentrations (0.01 mM) the uptake of (+)-methadone was higher than that of (-)-isomer indicating stereo-specificity of the uptake process. The uptake of (±)-methadone at low concentration (0.01 mM) was significantly inhibited by low temperature, lack of O2, lack of glucose, lack of Na+ in the incubation medium, and by exposure of the tissue to high temperature (≅100°C). The uptake was also inhibited by relatively high concentration of iodoacetate (1.0 mM) and of naloxone (1.0 mM). 6 Kinetic analysis of data showed that the diffusion constant for (±)-methadone was 5.0 (h−1) and the Vmax of the active transport process was 6.5 μmol g−1 h−1.