Pharmacokinetics, anticonvulsant efficacy and adverse effects of the beta-carboline abecarnil, a novel ligand for benzodiazepine receptors, after acute and chronic administration in dogs

Abstract

Abecarnil (ZK 112119; isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate), a novel beta-carboline with high affinity for central benzodiazepine (BZ) receptors, has been shown recently to be a potent anxiolytic and anticonvulsant in animal models whereas lacking ataxia-producing effects, a profile typical for a partial agonist at BZ receptors. In the present study abecarnil was tested in dogs after acute and chronic administration. Pharmacokinetic studies showed that abecarnil was eliminated rapidly after i.v. or p.o. administration, but elimination was delayed substantially after s.c. injection. After i.v. injection, the drug penetrated rapidly into the cerebrospinal fluid, but maximum concentrations reached in cerebrospinal fluid were only 6 to 8% of those in plasma. Anticonvulsant potency of abecarnil in dogs was studied by means of seizures induced by i.v. infusion of pentylenetetrazol. After i.v. administration of single doses, abecarnil was about half as potent as diazepam, dose-dependently increasing the pentylenetetrazol threshold by doses of 0.1-1 mg/kg. In contrast to diazepam, most dogs injected with abecarnil at anticonvulsant doses showed no ataxia. During chronic s.c. administration of abecarnil for 6 weeks, the anticonvulsant efficacy of the drug increased markedly during the first week(s) of treatment, possibly indicating drug accumulation in the brain. During the subsequent weeks of treatment, there was a slight reduction in anticonvulsant potency. No withdrawal symptoms were observed after cessation of the 6-week administration period. Furthermore, injection of the BZ antagonist Ro 15-1788 (flumazenil), 1 mg/kg i.v., after 5 weeks of treatment did not precipitate withdrawal symptoms except slight tremor in two of seven dogs studied.(ABSTRACT TRUNCATED AT 250 WORDS)