The potential role of lysosomes in tissue distribution of weak bases

Abstract

The potential importance of lysosomes as a site of accumulation of weak bases in tissues is discussed. A simple mathematical treatment predicts the quantitative significance of lysosomal trapping for monoacidic and diacidic weak bases. The features which are characteristics of lysosomal trapping are discussed, particularly in comparison with active transport and intracellular binding mechanisms. These features include: linear accumulation at low concentrations; nonlinearity at higher concentrations; dependence on structural integrity of tissue; energy dependence and competition with other weak bases. Subcellular distribution studies have previously shown that weak bases accumulate extensively in membranes; however, the dependence of accumulation on the structural integrity of tissue suggests that this is not the only significant mechanism of accumulation. The results of a range of studies of tissue distribution of weak bases are discussed to illustrate that these findings are consistent with accumulation in lung and liver being attributable to a combination of lysosomal trapping and accumulation in membranes whereas, in muscle, accumulation in membranes is the predominant mechanism of accumulation. The possible pharmacokinetic significance of lysosomal trapping of weak bases is also discussed.