J. Pitha et al., PARENTERAL HYDROXYPROPYL CYCLODEXTRINS - INTRAVENOUS AND INTRACEREBRAL ADMINISTRATION OF LIPOPHILES, Journal of pharmaceutical sciences, 83(6), 1994, pp. 833-837
Hydroxypropyl cyclodextrins are nontoxic carbohydrate derivatives of m
oderate molecular weight(1030-1750 Dal which form water-soluble comple
xes with many lipophiles. The fate of hydroxypropyl beta-cyclodextrin
alone and in complex with testosterone or cholesterol injected intrave
nously or intracerebrally into rats was followed. More than 90% of int
ravenously administered hydroxypropyl beta-cyclodextrin was cleared in
to urine in 4 h, as previously described (Monbaliu, J.; Van Beijsterve
ld, L.; Meuldermans, W.; Szathmary, S.; Haykants, J. Abstracts, 5th In
ternational Symposium on Cyclodextrins, Paris, 1990; Abstract 65). Aft
er the injection of steroids in complex with hydroxypropyl beta-cyclod
extrin into the tail vein of rats, the steroid component was released
from the complex, before it reached the kidneys; the release occurred
mainly into the proteins and lipoproteins of serum. Hydroxypropyl beta
-cyclodextrins injected alone into the brain were cleared within less
than 24 h, presumably via the flow of interstitial and cerebrospinal f
luids, and eventually were excreted in urine. Testosterone, incorporat
ed in a hydroxypropyl beta-cyclodextrin complex, after intracerebral i
njection was cleared from the brain even more rapidly than hydroxyprop
yl beta-cyclodextrin, presumably by crossing the blood-brain barrier a
nd later removal to the liver by the specific carrier proteins in seru
m. Complexed cholesterol, in a similar experiment, was largely retaine
d in the brain and its distribution there was uneven and remained that
way for at least 3 days. It is clear that lipophilic agents, after th
eir incorporation into hydroxypropyl beta-cyclodextrin complexes and s
ubsequent in vivo administration, are rapidly released and exchanged i
nto the plasma. In absence of plasma they enter tissues surrounding th
e injection site and thus are also promptly transferred into the organ
ism's lipid systems. The manner in which different lipophilic agents a
re transported in vivo appears not to be greatly affected by their pre
vious complexation; rather hydroxypropyl cyclodextrins just enable the
ir entry in a larger amount and in an exchangeable, nonaggregated form
.