COMPARATIVE-STUDIES OF THE FATE OF FREE AND LIPOSOME-ENTRAPPED HYDROXYPROPYL-BETA-CYCLODEXTRIN DRUG COMPLEXES AFTER INTRAVENOUS-INJECTION INTO RATS - IMPLICATIONS IN DRUG-DELIVERY/

Inclusion complexes of C-14-labelled hydroxypropyl-beta-cyclodextrin ( HP beta-CD) with tritiated dehydroepiandrosterone (DHEA), retinol (RET ) and dexamethasone (DEX) were entrapped in the aqueous phase of lipos omes composed of distearoyl phosphatidylcholine. Incubation of liposom e-entrapped complexes in the presence of rat blood plasma at 37 degree s C resulted in complex dissociation and drug leakage in the media at a rate which was minimal for DEX/HP beta-CD (11%), modest for RET/HP b eta-CD (23%) and considerable for DHEA/HP beta-CD (56%; 60 min). In co ntrast, the HP beta-CD moiety of the complexes was retained by liposom es quantitatively. Free complexes injected intravenously into rats wer e cleared rapidly from the circulation with most (up to 94%) of the HP beta-CD moiety recovered in 24 urine together with lesser and variabl e amounts of drug (up to 46% of the dose) in a pattern (DHEA < RET < D EX) that was consistent with the extent of drug association with HP be ta-CD in the presence of plasma. A significant proportion of the drugs (up to 25% of the dose) (but very little HP beta-CD) was removed by t he liver where drugs were catabolised rapidly, probably following comp lex dissociation and transport to the tissue via plasma proteins. Inje ction of entrapped complexes revealed that Liposomes alter their pharm acokinetics with only 6-13% of HP beta-CD and a moderate proportion of drugs (up to 26% of the dose) recovered in the urine. Much of the HP beta-CD moiety of the liposomal complexes was recovered in the liver ( up to 83%) and spleen (up to 13% of the dose) by 30 min after injectio n, together with a variable proportion of drugs in a pattern (DHEA < R ET < DEX) which reflected that of complex dissociation in vitro. Longe r term experiments where animals injected with liposome-entrapped comp lexes were killed at time intervals (up to 24 days), revealed that HP beta-CD is eliminated from the tissues, albeit at a very slow rate. Mo reover, the metabolism of individual drugs in the tissues following ve sicle disintegration, appeared to depend on the rate of complex dissoc iation with DEX, for instance, reaching values of 4-6% (liver) only af ter 14 days. It is concluded that administration of drug/cyclodextrin inclusion complexes via Liposomes could serve as a means to control th e action of a wide range of therapeutic agents.