THE CATIONIC LIPID STEARYLAMINE REDUCES THE PERMEABILITY OF THE CATIONIC DRUGS VERAPAMIL AND PROCHLORPERAZINE TO LIPID BILAYERS - IMPLICATIONS FOR DRUG-DELIVERY

The therapeutic activity of a wide variety of drugs is significantly i mproved when their longevity in the circulation is extended by encapsu lation in liposomes. To improve the retention of cationic drugs in lip osomes, we have investigated the effect of the cationic lipid stearyla mine on the permeability of the calcium channel blocker verapamil and the antipsychotic drug prochlorperazine, both of which are also multid rug resistance modulators. Both drugs were efficiently incorporated in to liposomes composed of DSPC/cholesterol that possessed a transmembra ne pH gradient (inside acidic). However, the efflux of the loaded drug s was relatively rapid (i.e., 50% of the encapsulated verapamil was re leased after 4 h at 37 degrees C), despite the presence of a 3 unit pH gradient (pH(i) = 4.0, pH(o) = 7.5). Drug retention within the liposo mes was improved by increasing the magnitude of the transmembrane pH g radient to approx. 5 units (pH(i) = 2.0, pH(o) = 7.5). Further improve ments in drug retention were achieved by the addition of 10 mol% of th e cationic lipid stearylamine in the DSPC/cholesterol liposomes. The c ombination of the 5 unit pH gradient and stearylamine resulted in incr eases of the retention of verapamil and prochlorperazine by approx. 20 - and 5-fold, respectively. Calculation of the permeability coefficien ts for the charged (cationic) and neutral forms of the drugs indicated that the neutral forms of both drugs were approx. 10(4)-fold more per meable than were the cationic forms of the drugs. Further, the presenc e of stearylamine reduced the permeability coefficient for the cationi c species of the drugs by approximately an order of magnitude, but had no effect on the neutral species of the drugs. The efflux curves obse rved for both verapamil and prochlorperazine could be mathematically m odeled by assuming that the primary influence of stearylamine was on t he development of a positive surface charge density on the inner monol ayer of the liposome. Taken in sum, these results indicate that steary lamine is effective at decreasing the leakage of cationic drugs from l iposomes, and may prove to be a valuable component of liposomal drug f ormulations.