INHIBITION BY VITAMIN-E OF DRUG ACCUMULATION AND OF PHOSPHOLIPIDOSIS INDUCED BY DESIPRAMINE AND OTHER CATIONIC AMPHIPHILIC DRUGS IN HUMAN CULTURED-CELLS

1 Cationic amphiphilic drugs (CADs) are widely used in chronic pharmac otherapies in spite of frequently observed side effects connected with lysosomal phospholipid (PL) storage. 2 It has recently been shown tha t alpha-tocopherol (alpha-Toc) inhibits drug- and PL accumulation in c ell cultures chronically exposed to the CAD, amiodarone. 3 The mechani sms of alpha-Toc action on drug kinetics and PL storage were studied i n human cultured fibroblasts exposed to single and repetitive doses of desipramine and other CADs. 4 alpha-Toc did not influence the initial , pH-dependent rapid phase of drug uptake. It inhibited, in a dose-dep endent manner, the slow and the cumulative phases of drug uptake and c oincidently the accumulation of cellular PLs. 5 The inhibitory effects of alpha-Toc on CAD and PL accumulations depends on the ratio between CAD and alpha-Toc concentrations in the medium. This points to compet ition between alpha-Toc and CADs for PL complex formation. 6 Effective ness of alpha-Toc on drug uptake varies among different CADs. It depen ds on its structural integrity but is independent of stereoisomerism. The inhibitory action is restricted to the piggyback slow drug uptake and therefore related to the proportion of membrane-mediated transport to permeation into lysosomes (rapid uptake). This proportion differs among CADs. 7 alpha-Toc prevents lysosomal membrane-PL storage, accele rates disintegration of PL-stores and normalizes drug-related increase d membrane fluidity. This strongly suggests that alpha-Toc restores me mbrane recycling, impaired by CAD exposure. 8 It remains to be tested in vivo whether alpha-Toc reduces CAD side effects without interfering with drug effectiveness.