THE CONTRIBUTION OF LYSOSOMAL TRAPPING IN THE UPTAKE OF DESIPRAMINE AND CHLOROQUINE BY DIFFERENT TISSUES

Cationic amphiphilic drugs strongly accumulate in tissues of different organs. Uptake is controlled by two major mechanisms, non-specific bi nding to membrane phospholipids, and ion-trapping within acidic cellul ar compartments. The aim of this study was to assess the individual co ntributions of these two mechanisms on the uptake in vitro of desipram ine and chloroquine into tissue slices of control and desipramine-trea ted mts. Drug uptake into intact slices was compared with uptake into slices with destroyed or non-functional acidic compartments. The seque nce of desipramine uptake by tissue slices of eight different organs w as: lungs>brain>hrart>diaphragm>kidneys>skeletal muscles>adipose tissu e>liver. The low desipramine concentration in liver may be due to meta bolism of the parent drug by cytochrome P-450. Uptake of chloroquine d iffered widely between slices of different organs with the sequence: l unes>kidneys=brain= liver>diaphragm=heart=skeletal muscles>adipose tis sue. Destruction or inactivation of the acidic compartments by homogen ization and freeze-thawing or by ammonium chloride, sodium fluoride, o r monensin, reduced drug uptake to similar extents. The reduction was organ-specific and may represent the size of the lysosomal compartment in the respective tissue cells. Uptake of chloroquine was more affect ed than that of desipramine, suggesting that ion-trapping: is the main factor for chloroquine accumulation, while binding to membrane phosph olipids, is the main factor for desipramine uptake. Single or multiple -dose treatments of rats with desipramine hardly had any effect on con secutive desipramine uptake into lung and liver slices, while the accu mulation of chloroquine was enhanced in these slices. In conclusion, t he extent of uptake of cationic amphiphilic drugs into tissue slices w as tissue-specific, and the contribution of the two uptake mechanisms was strongly drug-dependent.