Inhibition by vitamin E of drug accumulation and of phospholipidosis induced by desipramine and other cationic amphophilic drugs in human cultured cells

Abstract

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 cx-tocopherol (a-Toc) inhibits drug-and PL accumulation in cell cultures chronically exposed to the CAD, amiodarone. 3 The mechanisms of a-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 a-Toc did not influence the initial, pH-dependent rapid phase of drug uptake. It inhibited, in a dosedependent manner, the slow and the cumulative phases of drug uptake and coincidently the accumulation of cellular PLs. 5 The inhibitory effects of c-Toc on CAD and PL accumulations depends on the ratio between CAD and a-Toc concentrations in the medium. This points to competition between a-Toc and CADs for PL complex formation. 6 Effectiveness of a-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 a-Toc prevents lysosomal membrane-PL storage, accelerates disintegration of PL-stores and normalizes drug-related increased membrane fluidity. This strongly suggests that a-Toc restores membrane recycling, impaired by CAD exposure.8 It remains to be tested in vivo whether cx-Toc reduces CAD side effects without interfering with drug effectiveness.

Characterisation of the Binding of Cationic Amphiphilic Drugs to Phospholipid Bilayers Using Surface Plasmon Resonance

“…Of these CADs, CPZ exhibited the greatest uptake with respect to phospholipid interactions, whereas the largest interactions were observed for bilayers comprising DOPC. Previous studies have also demonstrated CPZ to have a greater interaction and thus uptake relative to AMI and PROP, [6,7,[10][11][12] presumably as CPZ is more hydrophobic. [12] Importantly, however, the boundaries of previous work have been extended, as two discrete binding processes were identified.…”

“…[19] This results in the formation of thread-like micelles, and finally formation of spherical micelles after approximately two hours. [19] It is postulated herein that the second process represents intercalation of each drug to form a drug-phospholipid complex, [11,20] www.chemmedchem.org as drugs did not dissociate completely from the membrane as evidenced by the residual response in SPR following exposure to the drug. Earlier studies have also attributed further intracellular accumulation of drugs with these drug-phospholipid complexes.…”

“…Earlier studies have also attributed further intracellular accumulation of drugs with these drug-phospholipid complexes. [11] It has been proposed that the formation of drug-phospholipid complexes mimics phospholipidosis, [7,18,20] a type of lipid storage disorder. [21] Essentially this phenomenon is related to the binding of CADs, whereby their hydrophilic and hydrophobic moieties inherently interact with the phosphate and alkyl chains of phospholipids to form a bulky lipophilic structure.…”

Characterisation of chlorpromazine binding to lipid bilayer membranes

“…Electron cryo-microscopy studies have also proposed that a drug from the same family as CPZ disrupts the bilayer by perturbation of the local organisation of phospholipids [21]. In the current study, it also postulated that the second process represents intercalation of each drug, forming a drug/phospholipid complex [22,23] as drugs did not dissociate completely from the membrane as evidenced by the residual response in SPR following exposure to the drug. It has been proposed that formation of drug/phospholipid complexes mimics phospholipidosis [14,19,23], a type of lipid storage disorder [24] which could give rise to the observed defects.…”

A Strategy for Risk Management of Drug-Induced Phospholipidosis

“…In vitro studies performed by Scuntaro et al (1996) showed that PL-CAD accumulation can be potentially inhibited by D-a-tocopherol (vitamin E). This research suggested that competition between vitamin E and drug for cell membranes prevented the formation of phospholipid-drug complexes.…”