Hydroxypropylcyclodextrins in parenteral use. II: Effects on transport and disposition of lipids in rabbit and humans.

Hydroxypropyl ethers of cyclodextrins, after parenteral administration, come into contact with lipids in tissues and in circulation and form water-soluble inclusion complexes with these lipids. A single intravenous administration of hydroxypropyl-beta-cyclodextrin to a hereditary hyperlipidemic Watanabe rabbit slightly and temporarily decreased the level of total cholesterol in serum. Single injections of hydroxypropyl-alpha-cyclodextrin and of the corresponding gamma-homologue, both of which are less potent solubilizers of cholesterol, had lesser effects. Repeated administration of hydroxypropyl-beta-cyclodextrin to rabbits led to a gradual increase in total cholesterol in circulation and eventually to a slight relief of atherosclerotic lesions in the thoracic aorta. The only untoward effects of repeated treatments (total doses of up to 40 g/kg) were vacuoles in cells of proximal convoluted tubules in the kidneys. Repeated administration also strongly increased cholesterol in urine, probably because of excretion of the soluble cholesterol-hydroxypropyl-beta-cyclodextrin complex. Proteins in urine increased significantly, whereas triglycerides increased only moderately after repeated administrations. Intravenous infusion of hydroxypropyl-beta-cyclodextrin into a patient with hypervitaminosis A led to a release of liver-stored retinoids into serum in quantities much higher than those that could be directly solubilized by hydroxypropyl-beta-cyclodextrin. Levels of total cholesterol in the circulation of this patient decreased during the infusion. Thus, hydroxypropylcyclodextrins may serve as artificial lipid carriers in the circulation, and because the exchanges that involve inclusion complexation occur very quickly, the presence of hydroxypropylcyclodextrins in organisms may catalytically augment the establishment of equilibria in lipid distribution.