title: Effect of cyclodextrin concentration on the oral bioavailability of danazol and cinnarizine in rats.
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.
authors.affiliation: Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. Electronic address: rhol@lundbeck.com.
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.affiliation: Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark; NSM, Research Unit for Functional Biomaterials, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark.
authors.forename: Niels Erik
authors.initials: NE
authors.lastname: Olesen
authors.affiliation: NSM, Research Unit for Functional Biomaterials, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark.
authors.forename: Rune A
authors.initials: RA
authors.lastname: Hartvig
authors.affiliation: Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
authors.forename: Erling B
authors.initials: EB
authors.lastname: Jørgensen
authors.affiliation: Discovery ADME, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
authors.forename: Dorrit B
authors.initials: DB
authors.lastname: Larsen
authors.affiliation: NSM, Research Unit for Functional Biomaterials, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Westh
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002936:Cinnarizine / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D003613:Danazol / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D005079:Excipients / Q000737:chemistry; D007408:Intestinal Absorption; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D005079:Excipients; D047392:beta-Cyclodextrins; D002936:Cinnarizine; D003613:Danazol
keywords: Cinnarizine; Complexation; Cyclodextrins; Danazol; In vivo; Rats