BETA-CYCLODEXTRIN DERIVATIVES, SBE4-BETA-CD AND HP-BETA-CD, INCREASE THE ORAL BIOAVAILABILITY OF CINNARIZINE IN BEAGLE DOGS

The absolute bioavailabilities (F-abs) of cinnarizine after oral administration as two modified beta-cyclodextrin (SBE4-beta-CD or HP-beta-CD) solutions, an aqueous suspension, and two capsules in fasted beagle dogs were determined. Cinnarizine was administered orally (25.0 mg) and intravenously (12.5 mg) to four dogs. Blood samples were drawn for 24.5 h postdosing, and cinnarizine levels in plasma were determined by HPLC with spectrofluorometric detection. Cinnarizine pharmacokinetics after iv administration as a 1.25 mg/mL SBE4-beta-CD solution followed triexponential behavior (t(1/2) = 12.6 +/- 0.4 h and Cl = 1.4 +/- 0.17 L/h/kg). A very low bioavailability of cinnarizine with a wide interanimal variation was observed after oral administration as a suspension (F-abs = 8 +/- 4%) or capsule containing only cinnarizine (F-abs = 0.8 +/- 0.4%) Administration of cinnarizine as a CD complex either as a solution (F-abs = 55-60%) or in a capsule (F-abs = 38 +/- 12%) significantly enhanced the bioavailability. Since the solutions showed excellent bioavailability, the logical conclusion is that, once presented as a solution, cinnarizine is well absorbed and that cinnarizine rapidly dissociates from its inclusion complexes. Presumably, the elevated bioavailability from the SBE4-beta-CD containing capsule was due to rapid dissolution and release of cinnarizine.