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 pharmacotherapies in spite of frequently observed side effects connected with lysosomal phospholipid (PL) storage. 2. It has recently been shown that alpha-tocopherol (alpha-Toc) inhibits drug- and PL accumulation in cell cultures chronically exposed to the CAD, amiodarone. 3. The mechanisms of alpha-Toc action on drug kinetics and PL storage were studied in 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-dependent manner, the slow and the cumulative phases of drug uptake and coincidently 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 competition between alpha-Toc and CADs for PL complex formation. 6. Effectiveness of alpha-Toc on drug uptake varies among different CADs. It depends 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, accelerates disintegration of PL-stores and normalizes drug-related increased membrane fluidity. This strongly suggests that alpha-Toc restores membrane 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.
Scuntaro
I
I
Department of Pharmacology, University of Bern, Switzerland.
Kientsch
U
U
Wiesmann
U N
UN
Honegger
U E
UE
D000929:Antidepressive Agents, Tricyclic / Q000009:adverse effects* / Q000378:metabolism; D002412:Cations; D002478:Cells, Cultured; D003470:Culture Media; D003891:Desipramine / Q000009:adverse effects* / Q000378:metabolism; D006801:Humans; D008064:Lipidoses / Q000139:chemically induced / Q000517:prevention & control*; D010743:Phospholipids / Q000378:metabolism*; D014810:Vitamin E / Q000378:metabolism / Q000494:pharmacology*
D000929:Antidepressive Agents, Tricyclic; D002412:Cations; D003470:Culture Media; D010743:Phospholipids; D014810:Vitamin E; D003891:Desipramine