Characterization of (±)‐methadone Uptake by Rat Lung

Abstract

1By use of a sensitive and specific fluorescence assay procedure it was shown that after subcutaneous administration to rats, (±)rmethadone 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 (±)rmethadone 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 02, lack of glucose, lack of Na+ in

Use of Plasma and Brain Unbound Fractions to Assess the Extent of Brain Distribution of 34 Drugs: Comparison of Unbound Concentration Ratios to in Vivo P-Glycoprotein Efflux Ratios

“…Methadone is a substrate for active uptake in the lung (Chi and Dixit, 1977), so it is plausible methadone also may undergo active uptake across the BBB. The [plasma], u /[brain], u ratio predicted that loperamide alone would have substantially reduced central activity, whereas the P-gp efflux ratio predicted that both loperamide and methadone would evidence substantially reduced central activity.…”