COMPARATIVE-STUDIES OF THE FATE OF FREE AND LIPOSOME-ENTRAPPED HYDROXYPROPYL-BETA-CYCLODEXTRIN DRUG COMPLEXES AFTER INTRAVENOUS-INJECTION INTO RATS - IMPLICATIONS IN DRUG-DELIVERY/
B. Mccormack et G. Gregoriadis, COMPARATIVE-STUDIES OF THE FATE OF FREE AND LIPOSOME-ENTRAPPED HYDROXYPROPYL-BETA-CYCLODEXTRIN DRUG COMPLEXES AFTER INTRAVENOUS-INJECTION INTO RATS - IMPLICATIONS IN DRUG-DELIVERY/, Biochimica et biophysica acta (G). General subjects, 1291(3), 1996, pp. 237-244
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.