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Effect of desmethylimipramine on the kinetics of chlorphentermine accumulation in isolated perfused rat lung.

A number of basic amines are preferentially accumulated by the lung and there is the possibility that drug interactions in this organ may be important in vivo. In this study, the kinetics of the accumulation process for chlorphentermine were examined in a "single pass" isolated perfused rat lung. Chlorphentermine (2.5 x 10-7-2.5 x 10-5 M) was rapidly taken up over the 10-min perfusion period, and the rate of uptake was well described by a biexponential equation. One component of the uptake was small in capacity and nonsaturable while the other was large in capacity and saturable. The smaller component could not be explained solely by distribution into total lung water. When desmethylimipramine (10-6-10-3 M) was added to the perfusate, it had little effect on the nonsaturable component but markedly affected the other; the initial velocity of uptake was decreased and the (negative) rate of change of uptake was increased with increased desmethylimipramine concentration. The data suggested that there were at least two mechanisms involved in uptake of chlorphentermine: a saturable transport process and tissue binding. It is not clear without further work whether the transport saturability is a mainfestation of a carrier-mediated process or of drug-induced membrane changes affecting diffusion.