Excretion and metabolism of flunarizine in rats and dogs.
The excretion and metabolism of (E)-1-[bis(4-fluorophenyl)methyl]-4-(3-phenyl-2-propenyl)piperazine dihydrochloride (flunarizine hydrochloride, R 14 950, Sibelium) were studied after single oral doses in rats and dogs, using tritium-labelled as well as 14C-labelled drug. Flunarizine was well absorbed in both species. The mass balance for the unchanged drug and its major metabolites in urine, bile and faeces, as estimated with radio-HPLC, ALLOWED an explanation of the differences observed for the excretion pattern of the radioactivity in flunarizine-14C and flunarizine-3H dosed rats, and in male and female rats. Main metabolic pathway in male rats was the oxidative N-dealkylation resulting in bis(4-fluorophenyl)methanol and a number of complementary metabolites of the cinnamylpiperazine moiety, of which hippuric acid was the main one. In female rats and male dogs, however, hydroxy-flunarizine was the main metabolite, resulting from the aromatic hydroxylation of the phenyl ring of the cinnamyl moiety. Enterohepatic circulation of bis(4-fluorophenyl)methanol and hydroxy-flunarizine was proved by "donor-acceptor" coupling in rats; in bile and urine, these two metabolites were present mainly as glucuronides. The glucuronide of hydroxy-flunarizine was also the main plasma metabolite in dogs.
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002936:Cinnarizine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism* / Q000652:urine; D004285:Dogs; D005260:Female; D005444:Flunarizine; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D010879:Piperazines / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
D001798:Blood Proteins; D010879:Piperazines; D002936:Cinnarizine; D005444:Flunarizine