NEW INJECTABLE AQUEOUS CARBAMAZEPINE SOLUTION THROUGH COMPLEXING WITH2-HYDROXYPROPYL-BETA-CYCLODEXTRIN - TOLERABILITY AND PHARMACOKINETICSAFTER INTRAVENOUS-INJECTION IN COMPARISON TO A GLYCOFUROL-BASED FORMULATION

The poor water solubility of the antiepileptic drug (AED) carbamazepin e (CBZ) is generally considered an absolute contraindication to parent eral administration in epileptic patients. However, the water solubili ty of CBZ can be largely enhanced through formation of an inclusion co mplex with an amorphous cyclodextrin derivative, 2-hydroxypropyl-beta- cyclodextrin (HP beta CD). We studied tolerability and pharmacokinetic s of an aqueous CBZ:HP beta CD solution after intravenous (i.v.) admin istration in dogs. For comparison, a conventional glycofurol-based sol ution of CBZ was used. We also administered a commercial liquid formul ation of CBZ orally (p.o.). Infusion of CBZ:HP beta CD solutions or HP beta CD ''placebo'' formulations i.v. was well tolerated by the anima ls. In contrast, infusion of CBZ:glycofurol solutions and glycofurol p lacebo solutions induced marked behavioral and cardiovascular adverse effects. Pharmacokinetic studies indicated that glycofurol inhibited C BZ metabolism by decreasing formation of the major CBZ metabolite CBZ- 10,11-epoxide (CBZ-E). With infusion of CBZ:HP beta CD 10 ml/min for 1 2-15 min, resulting in a CBZ dose of CBZ 5 mg/kg body weight, peak CBZ plasma levels of similar to 3.6 mu g/ ml were obtained, This relative ly low peak concentration is primarily due to the rapid elimination of CBZ in dogs [half-life (t1/2) < 1 h]. Comparison of peak plasma level s determined after p.o. administration of CBZ to dogs with peak CBZ le vels previously determined after p.o. administration in humans indicat ed that about four times higher doses are needed in dogs to attain the same peak plasma levels as in humans. In view of previous experimenta l data showing rapid penetration of CBZ into brain, our results indica te that aqueous CBZ:HP beta CD solutions might be ideally suited for p arenteral use in acute clinical conditions such as status epilepticus (SE), particularly because CBZ is a drug with only minor respiratory o r cardiovascular effects.