Membrane interactions of some catamphiphilic drugs and relation to their multidrug-resistance-reversing ability.
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- and cis-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 of trans- and cis-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.
Medicinal-Pharmaceutical Chemistry, Borstel Research Institute, Germany.
I K
IK
Pajeva
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M
Wiese
H P
HP
Cordes
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JK
Seydel
D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002152:Calorimetry, Differential Scanning; D018492:Dopamine Antagonists / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D005475:Flupenthixol / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008567:Membranes, Artificial; D051379:Mice; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D014700:Verapamil / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D018492:Dopamine Antagonists; D006571:Heterocyclic Compounds; D008567:Membranes, Artificial; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D004317:Doxorubicin; D014700:Verapamil; D005475:Flupenthixol; D000638:Amiodarone