Drugs-in-cycle dextrins-in-liposomes: an approach to controlling the fate of water insoluble drugs in vivo

Distearoyl phosphatidycholine liposomes containing entrapped complexes of C-14-labelled hydroxypropyl-beta-cyclodextrin (HP beta-CD) with H-3-labelled dehydroepiandrosterone (DHEA), retinol (RET) and dexamethasone (DEX) were prepared and incubated with rat blood plasma at 37 degrees C. The rate of drug dissocation and release in the media was minimal for DEX/HP beta-CD (11%), modest for RET/HP beta-CD (23%) and considerable for DHEA/HP beta-CD (56%, 60 min). However, the HP beta-CD moiety of each of the complexes was retained by liposomes quantitatively. Intravenous injection of free complexes into rats led to their rapid clearance from the circulation with up to 94% of HP beta-CD recovered in 24 h urine together with lesser and variable amounts of drug (up to 46% of the dose, DHEA < RET < DEX). A proportion of the drugs (up to 25% of the dose), but very little HP beta-CD, was removed by the liver where drugs were catabolised rapidly, presumably following complex dissociation in the blood and drug transport to the tissue via plasma proteins. After injection of complexes entrapped in liposomes, these were found to alter the pharmacokinetics of the complexes with only 6-13% of HP beta-CD and a moderate proportion of drugs (up to 26% of the dose) recovered in 24 h urine. Much of the HP beta-CD moiety was recovered in the liver (up to 83%) and spleen (up to 13% of the dose) 30 min after injection, together with a variable proportion of drugs (DHEA < RET < DEX). In longer term (up to 24 days) experiments with liposome-entrapped complexes, there was removal of HP beta-CD from the tissues albeit at a very slow rate. Moreover, the metabolism of individual drugs, both the liver and spleen following vesicle disintegration appeared to depend directly on the rate of complex dissociation. Administration of drug/cyclodextrin inclusion complexes via liposomes could serve as a means to control the action of a wide range of therapeutic agents. (C) 1998 Elsevier Science B.V. All rights reserved.