Pharmacokinetics of bromerguride, a new dopamine-antagonistic ergot derivative in rat and dog.

Abstract

Bromerguride is a novel dopamine antagonistic ergot derivative in which a complete reversed pharmacodynamic profile has been obtained by bromine substitution at position 2 as compared to dopamine agonistic lisuride. The pharmacokinetics of the new drug has been investigated following i.v. and i.g. administration of the 14C-labelled compound to rat (R) and beagle dog (D) with regard to drug registration requirements and to serve other preclinical disciplines (toxicology, pharmacology). Because of incomplete absorption the oral bioavailability was approx. 40% at dose levels of 0.25 mg/kg (R, D) and 4 mg/kg (D) and 20% after i.g. dosing of 5 mg/kg (R). Most of the 14C-label in plasma consisted of unchanged bromerguride apart from small amounts of the N-monodesethyl metabolite, which was also obtained as a biodegradation product in a rat liver perfusion experiment. Bromerguride plasma levels declined with half-lives of 0.7 h and 9 h (R) and 0.2 h and 2.7 h (D) after i.v. treatment. Peak levels in rat brain and plasma were observed within 1-2 h after oral dosing; brain levels accounting for 1/10 of bromerguride plasma levels. Whole body autoradiographs in rat demonstrated that the 14C-label was rapidly distributed into tissues and organs, readily passed the blood-brain and the placental barrier. Bromerguride was excreted to less than 10% unchanged with urine. Excretion was mainly biliary. Most of the 14C-label was recovered in the excreta within 24 h postdose.