POSSIBLE PHARMACOKINETIC AND PHARMACODYNAMIC FACTORS AFFECTING PARKINSONISM INDUCEMENT BY CINNARIZINE AND FLUNARIZINE

Potentialities of cinnarizine diphenylmethyl)-4-(3-phenyl-2-propenyl)p iperazine, CZ] and its fluorine derivative flunarizine ophenyl)-methyl ]-4-(3-phenyl-2-propenyl)piperazine FZ] to induce parkinsonism as an a dverse effect were evaluated pharmacokinetically and pharmacodynamical ly in rats. In multiple-dose experiments, CZ or FZ was given to rats a t a daily dose of 20 mu mol/kg for 1, 5, 10, 15, and 30 days, and CZ, FZ, and the ring-hydroxylated metabolites of their cinnamyl moiety hyl )-4-[3-(4'-hydroxyphenyl)-2-propenyl]piperazine C-2 and ethyl]-4-[3-(4 '-hydroxyphenyl)propenyl]piperazine, F-2] in the plasma and striatum w ere determined 24 hr after the final dose. Plasma and striatum concent rations of the above compounds except for FZ reached steady state afte r 10 doses, but their concentrations of FZ continued to increase throu ghout the experiments. The concentrations obtained after the 30 doses were in the order of FZ > F-2 > CZ > C-2 for the plasma and of F-2 > F Z > CZ > C-2 for the striatum. The ratios of striatum to plasma concen trations of C-2 and F-2 were 2.4 and 3 times higher than those of the parent drugs. Binding affinities of CZ, FZ, and their 10 metabolites f or rat striatal dopamine D-2 receptors (D2-R) were assessed by competi tive radioligand-binding studies using idinyl]-5-chloro-2-methoxy-4-me thylamino-benzamide ([H-3]-YM-09151-2). The IC(50)s calculated from th eir Ki values were in the order of F-2 < C-2 < FZ < CZ < C-4 much less than F-1, indicating that C-2 and F-2 exhibit higher affinities for D 2-R than the parent drugs, whereas affinities of other metabolites wer e 1 to 2 orders of magnitude less than those of C-2 and F-2. These res ults suggest some important roles of C-2 and F-2 in the development of parkinsonism as active metabolites during chronic medication with CZ and FZ, respectively.