PARENTERAL HYDROXYPROPYL CYCLODEXTRINS - INTRAVENOUS AND INTRACEREBRAL ADMINISTRATION OF LIPOPHILES

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 .