CONTROL OF PLASMA CHOLESTEROL-LOWERING ACTION OF PROBUCOL WITH VARIOUS LIPID CARRIER SYSTEMS

In order to explore the relationship between the pharmacokinetic prope rties and pharmacological actions of lipophilic drugs injected with li pid carrier systems, probucol as selected as a model drug with high li pophilicity, and the effect of disposition control on cholesterol-lowe ring activities was evaluated. Both large emulsion, with mean diameter of 280 nm, and long-circulating type small emulsion containing egg sp hingomyelin with mean diameter of 100 nm, showed stable incorporation of probucol. The former produced rapid accumulation of probucol in the liver, while the latter demonstrated prolonged systemic circulation a nd gradual hepatic uptake. On the other hand, inject-ion of a micella solution with HCO-60 (polyoxyethylene hydrogenated castor oh) showed a rapid decrease in plasma concentration and a high hepatic uptake of p robucol, similar to injections with serum, suggesting the rapid releas e of the drug from the micelles, However, probucol in a micellar solut ion showed higher cholesterol-lowering action than that in emulsion fo rmulations. These results suggested that the pharmacological action of probucol in the liver might be affected by the uptake mode and sequen tial disposition in the organ, depending on the drug retention propert ies of the lipid carrier particles.