PARTITION OF DOPAMINE ANTAGONISTS INTO SYNTHETIC LIPID BILAYERS - THEEFFECT OF MEMBRANE-STRUCTURE AND COMPOSITION

Partition coefficients, K(p), of four dopamine antagonists (pimozide, fluspirilene, haloperidol and domperidone) between the aqueous phase a nd lipid bilayer vesicles were determined as a function of lipid chain length, unsaturation and temperature encompassing the range of the li pid phase transition. Model membranes of egg phosphatidylcholine (PC), dimyristoyl (DMPC)-, dipalmitoyl (DPPC)-, distearoyl (DSPC)- and diol eoyl (DOPC)-phosphatidylcholines were studied. K(p) values of the drug s are different in the various membranes under study and depend on tem perature, aliphatic carbon chain-length and on the presence of unsatur ation in the aliphatic lipid chain. First-order transition of membrane lipids from the gel to the liquid crystalline state is accompanied by a sharp increase of the partition coefficient of pimozide and fluspir ilene in DMPC, DPPC and DSPC bilayers. For domperidone, K(p) values ar e maximal within the mid-point of phase transition of DMPC and DPPC, w hile for DSPC K(p) values increase progressively with increasing tempe rature. Haloperidol K(p) values display a maximum at the mid-point of phase transition of DMPC, while a progressive increase of K(p) is obse rved in DPPC and DSPC. The four drugs are easily accommodated in bilay ers of short aliphatic chain lipids (DMPC), the partition coefficients being 17 137 for pimozide, 18 700 for fluspirilene, 686 for domperido ne and 722 for haloperidol, at temperatures 10-degrees-C below the mid -point of the lipid phase transition. Except for haloperidol, the part ition of the drugs in DOPC (18:1) is higher than that in DSPC (18:0) b ilayers at a temperature above the phase transition temperature of bot h lipids. From our experiments we can conclude that artificial membran es are useful models to understand the physicochemical mechanisms invo lved in the interaction of dopamine antagonists with biological membra nes.