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. 1996 Jan;122(1):27–40. doi: 10.1007/BF01203070

Membrane interactions of some catamphiphilic drugs and relation to their multidrug-resistance-reversing ability

I K Pajeva 1, M Wiese 1, H -P Cordes 1, J K Seydel 1,✉
PMCID: PMC12201749  PMID: 8543589

Abstract

The multidrug-resistance (MDR)-reversing ability of the catamphiphilic drugs could be mediated through their interaction with the membrane phospholipids. This could lead directly (through changes in membrane permeability and fluidity) and/or indirectly (through inhibition of P-glycoprotein phosphorylation via inhibition of the phosphatidylserine-dependent protein kinase C or changes in the conformation and functioning of the membrane-integrated proteins via changes in the structure organization of the surrounding membrane bilayer) to the reversal of MDR. Using differential scanning calorimetry and NMR techniques and artificial membranes composed of phosphatidylcholine or phosphatidylserines we found a significant correlation between the MDR-reversing activity of the drugs in doxorubicin-resistant human breast carcinoma MCF-7/DOX and murine leukaemia P388/DOX tumour cells (data taken from the literature) and their ability to interact with phosphatidylserines.Trans- andcis-flupentixol were found to interact most strongly with both the phospholipids, followed by trifluoperazine, chlorpromazine, triflupromazine, flunarizine, imipramine, quinacrine and lidocaine. Differences in the interaction oftrans- andcis-flupentixol with the phospholipids studied are suggested to be responsible for their different MDR-reversing ability. Verapamil showed moderate membrane activity, assuming that the membrane interactions are not the only reason for its high MDR-reversing ability. Amiodarone showed very strong interactions with phosphatidylserines and is recommended for further MDR-reversal studies.

Key words: MDR modulation mechanisms, Catamphiphilic MDR modifiers, Drug/membrane interactions, Artificial membranes, DSC and NMR measurements

Abbreviations

MDR

multidrug resistance

P-gp

P-glycoprotein

PKC

protein kinase C

DSC

differential scanning calorimetry

NMR

nuclear magnetic resonance

DOX

doxorubicin

DMSO

dimethylsulphoxide

D2O2

deuterium oxide

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