Effect of cyclodextrin concentration on the oral bioavailability of danazol and cinnarizine in rats

René Holm, Niels Erik Olesen, Rune A. Hartvig, Erling B. Jørgensen, Dorrit Bjerg Larsen, Dorrit B Larsen, Peter Westh
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V · 2016 · vol. 101 , pp. 9–14 · doi:10.1016/j.ejpb.2016.01.007 · PMID:26776271 · W2284564108
Lab / animal OA: closed CC0 ⤵ 3 in-corpus citations
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Increasing cyclodextrin concentration reduced danazol bioavailability in rats but had no significant effect on cinnarizine pharmacokinetics.

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Abstract

Cyclodextrins (CDs) are frequently used as an excipient to enhance the intestinal drug absorption of compounds with a low aqueous solubility. However, there exists an intricate interplay between opposing effects that determine the optimal dosing criterion. These opposing effects are the benefits of circumventing the dissolution time required to dissolve the non-absorbable drug particles in the intestine versus the disadvantage of decreasing the concentration of the drug available to permeate the intestinal membrane if excessive CD concentrations are used. This study investigated whether there is a potential risk of overdosing CDs in aqueous formulations resulting in suboptimal bioavailability. This was done by measuring the in vivo pharmacokinetics of danazol, which has a high affinity for hydroxypropyl-βCD, and cinnarizine, which has a pH-dependent low to medium affinity. Pharmacokinetic studies of danazol in rats showed a significant longer Tmax and decreased Cmax resulting in decreased bioavailability when the CD concentration was increased. No significant difference was seen for any of the pharmacokinetic parameters for cinnarizine as a function of CD dose. The present study thus demonstrates that surplus CD concentrations can have a major effect on the pharmacokinetic profile of one compound and a minor effect on the pharmacokinetic profile of another. This suggests that there are some compounds where the CD excipient should be used with care and others where it can be used without major concerns.

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MeSH descriptors

beta-Cyclodextrins Cinnarizine Cinnarizine Danazol Danazol Administration, Oral Animals beta-Cyclodextrins Biological Availability Chemistry, Pharmaceutical Chemistry, Pharmaceutical Cinnarizine Cinnarizine Danazol Danazol Excipients Excipients Intestinal Absorption Male Rats

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