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 14C-labelled hydroxypropyl-beta-cyclodextrin (HP beta-CD) with tritiated dehydroepiandrosterone (DHEA), retinol (RET) and dexamethasone (DEX) were entrapped in the aqueous phase of liposomes composed of distearoyl phosphatidylcholine. Incubation of liposome-entrapped complexes in the presence of rat blood plasma at 37 degrees 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 beta-CD (23%) and considerable for DHEA/HP beta-CD (56%; 60 min). In contrast, the HP beta-CD moiety of the complexes was retained by liposomes quantitatively. Free complexes injected intravenously into rats were cleared rapidly from the circulation with most (up to 94%) of the HP beta-CD moiety recovered in 24 urine together with lesser and variable amounts of drug (up to 46% of the dose) in a pattern (DHEA < RET < DEX) that was consistent with the extent of drug association with HP beta-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 the liver where drugs were catabolised rapidly, probably following complex dissociation and transport to the tissue via plasma proteins. Injection of entrapped complexes revealed that liposomes alter their pharmacokinetics 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 injection, together with a variable proportion of drugs in a pattern (DHEA < RET < DEX) which reflected that of complex dissociation in vitro. Longer term experiments where animals injected with liposome-entrapped complexes 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. Moreover, the metabolism of individual drugs in the tissues following vesicle disintegration, appeared to depend on the rate of complex dissociation with DEX, for instance, reaching values of 4-6% (liver) only after 14 days. It is concluded that administration of drug/cyclodextrin inclusion complexes via liposomes could serve as a means to control the action of a wide range of therapeutic agents.
McCormack
B
B
Centre for Drug Delivery Research, School of Pharmacy, University of London, UK.
Gregoriadis
G
G
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D003505:Cyclodextrins / Q000008:administration & dosage*; D003687:Dehydroepiandrosterone / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D003907:Dexamethasone / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D004337:Drug Carriers; D007275:Injections, Intravenous; D008081:Liposomes; D051381:Rats; D017208:Rats, Wistar; D014801:Vitamin A / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D004337:Drug Carriers; D008081:Liposomes; D047392:beta-Cyclodextrins; D014801:Vitamin A; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D003687:Dehydroepiandrosterone; D003907:Dexamethasone