[Metabolic pathways of dipfluzine in rats].

AIM: To investigate the metabolic pathways of dipfluzine in rats. METHODS: After an oral dose of dipfluzine (80 mg x kg(-1)) to rats, urine was collected for 12 h. The metabolites of dipfluzine in urine were chromatographed and identified by LC/DAD/MS methods. RESULTS: In the rat urine, there were 1-(4-fluorophenyl)-4-piperazinylbutanone and its glucuronide, 4-hydroxybenzophenone and its glucuronide, 4-fluoro-gamma-hydroxybenzenebutanoic acid and its glucuronide and sulfate, diphenylmethanol and its glucuronide, dipfluzine, and benzophenone. CONCLUSION: In rats, dipfluzine was mainly metabolized in the pathways of N-desalkylation at 1- and 4-positions of piperazine ring. Some of metabolites were further conjugated with glucuronic acid and/or sulfuric acid.

Sensitive gas chromatographic method for the determination of cinnarizine and flunarizine in biological samples.

A sensitive method has been developed for the determination of the vasoactive compounds cinnarizine and flunarizine in plasma, urine and milk samples from man and animals. The procedure involves the extraction of the drugs and their internal standard from the biological samples at alkaline pH, back-extraction into sulphuric acid and re-extraction into the organic phase (heptane-isoamyl alcohol). The analyses were carried out by gas chromatography using a nitrogen-selective thermionic specific detector. The detection limit was 0.5 ng/ml of biological fluid and extraction recoveries were sufficiently high (87-94%). The method was applied to plasma samples from bioavailability studies of both cinnarizine and flunarizine in healthy volunteers, and to plasma, urine and milk samples from flunarizine-treated dogs.

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.

Determination of the calcium antagonist flunarizine in biological fluids by gas-liquid chromatography.

A method is described for the quantitation of flunarizine in biological fluids including plasma, urine, milk, fecal and tissue homogenates using the analogue cinnarizine as the internal standard. As little as 1.5 ng of flunarizine per ml of plasma can be accurately quantitated, this being achieved by the combination of a selective extraction procedure and a nitrogen detector. The method has been used to determine the concentration of flunarizine in biological fluids in support of human and animal pharmacokinetic studies.