Safety of oral cyclodextrins: effects of hydroxypropyl cyclodextrins, cyclodextrin sulfates and cationic cyclodextrins on steroid balance in rats.

Derivatives of beta-cyclodextrin differing in the length of a hydroxyalkyl substituent (CH2CH2OH, CH2CHOHCH3, CH2CHOHCH2CH2CH2CH3) or in the electrical charge of the substituents (SO4-, CH2CHOHCH2N(CH3)3+) and hydroxypropyl derivatives (CH2CHOHCH3) of alpha-, beta-, and gamma-cyclodextrin were compared, individually and in mixtures, as solubilizers of cholesterol. The most effective solubilizer proved to be hydroxypropyl derivatives of beta-cyclodextrin; beta-cyclodextrin sulfate (SO4-) was practically devoid of solubilizing activity. Oral administration of these cyclodextrin derivatives, some of which are both nondegradable and effective complexation agents for cholesterol and bile acids, nevertheless did not affect the conversion of [14C]acetic acid to [14C]-cholesterol in rat under the same conditions when another bile acid complexation agent, cholestyramine, increased that conversion. Thus, complexation of cholesterol and of bile acids by cyclodextrin derivatives, which is a significant and well-defined phenomenon in vitro, seems to have limited importance in terms of excretion of cholesterol from the gastrointestinal tract. It is proposed that various untoward effects observed after chronic large oral doses of hydroxypropyl beta-cyclodextrin are administered are not caused by an increased excretion of some vital lipophile or enzyme but are probably caused by solubilization and increased absorption of toxic contaminants of the ingested food.