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Abstract

The inclusion complex formation of intravenously administered hydroxypropyl-beta-cyclodextrin and beta-cyclodextrin with endogenous lipids was studied. We tested the hypothesis that complex formation of endogenous cholesterol with cyclodextrins in the bloodstream leads to extraction of cholesterol from the large lipoprotein particles. The relatively small cholesterol-cyclodextrin complexes then leave the bloodstream via capillary pores, and dissociation of the complex in the extravascular compartment finally causes redistribution of cholesterol from blood to tissue. This hypothesis is supported by the following experimental findings. Intravenous administration of cyclodextrins led to a transient decrease in plasma cholesterol levels in a dose-dependent manner, and in vitro cholesterol-cyclodextrin complexes passed dialysis membranes with a molecular weight cutoff of 6000-8000. Further, cyclodextrins increased protein binding of the steroidal drug spironolactone, probably through removal of cholesterol from plasma protein binding sites. Finally, extravascular redistribution was directly demonstrated in histological studies of the kidneys. Glomerular filtration of the cholesterol-cyclodextrin complex is followed by dissociation of the complex in the ultrafiltrate, resulting in cholesterol accumulation in the proximal tubule cells. The cholesterol-beta-cyclodextrin complex has a limited aqueous solubility. Crystallization of this complex in renal tissue might explain the nephrotoxicity of parenterally administered beta-cyclodextrin. The absence of such crystallization might explain the lower nephrotoxicity of hydroxypropyl-beta-cyclodextrin after intravenous administration.

Molecular Mechanism of Cyclodextrin Mediated Cholesterol Extraction

“…Experimentally it is difficult to distinguish between the 2∶1 and 1∶1 complexes, and different methods predict binding constants varying over orders of magnitude. Keeping these limitations in mind, a comparison of the binding constants calculated from our PMFs predict an order of magnitude comparable to the experimental estimate [33], [34] for -CD and HP--CD, assuming the experiments probe the 2∶1 stoichiometry. In experiments on DM--CD [35], the binding affinity could be differentiated between the 2∶1 and 1∶1 stoichiometries; the 2∶1 case showed a much higher affinity in line with our results for -CD (See Text S1 for details)…”

Thermotropic and Spectroscopic Behavior of Skin: Relationship with Percutaneous Permeation Enhancement

“…However, the transmission electron microscopic visualization of the lipid matrix showed no changes in the organization of lipids in the intercellular spaces after treatment with aqueous solution of β-and γ-CyD, whereas treatment with hydroxypropyl-β-CyD produced significant change in the lamellar structure [25]. Frijlink et al [183] have reported formation of stable complexes with endogenous cholesterol in the bloodstream by hydroxypropyl-β-CyD. Similarly, Legendre et al reported the extraction of approximately 10% cholesterol and proteins by hydroxypropyl-β-CyD from the SC [182].…”

Pharmaceutical Applications of Cyclodextrins. 2. In Vivo Drug Delivery

“…Using cyclodextrins to potentially remove agents such as cholesterol 54,57,114,115 and vitamin A 45,51,116,117 from the body have proven to be useful. These observations may imply that, since cyclodextrins are capable of removing unwanted agents from the body, they might also remove essential materials.…”