[Pharmacokinetics and biotransformation of the analgesic flupirtine in the rat and dog]

Abstract

Pharmacokinetics and biotransformation of 14C-labelled ethyl-N-[2-amino-6-(4-fluorophenylmethylamino)pyridin-3-yl]carbama te maleate (flupirtine maleate, D 9998 maleate) was studied in rats and dogs. The drug was rapidly and completely absorbed after peroral administration in both species. The kinetics of the plasma levels after intravenous administration show a short distribution phase followed by an elimination phase with half-lives between 2 and 3 h. Similar half-lives were observed after peroral administration: 2.2. h in the rat and 2.6 h in the dog. Renal excretion amounts to 20% (rat) and 36% (dog) after i.v. administration, and to 22% (rat) and 35% (dog) after p.o. administration. The major part of the dose is excreted via the feces. The drug is reversibly distributed to the tissues. Similar concentrations appear in the well perfused organs. A brain/plasma concentration ratio of greater than or equal to 1 was found and is a favourable prerequisite for a centrally acting analgesic. Insight in the biotransformation pathways of 14C-flupirtine maleate was obtained by structure determination of urinary metabolites. The urinary radioactivity of the rat consisted practically exclusively of p-fluoro-hippuric acid that is generated by an oxydative metabolic degradation of flupirtine. Dog urine, too, contains this metabolite, however, accompanied by the drug excreted unchanged and by a further metabolite structurally still very similar to flupirtine. The latter metabolite is formed via acetylation of an in vivo hydrolysis product of flupirtine and retains 1/4 of the analgesic potency of flupirtine. Regarding the patterns of excretion and of biotransformation the dog represents an intermediate between rat and man.