Abstract
Potentialities of cinnarizine [1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine, CZ] and its fluorine derivative flunarizine [1-[bis(4-fluorophenyl)-methyl]-4-(3-phenyl-2-propenyl)piperazine, FZ] to induce parkinsonism as an adverse effect were evaluated pharmacokinetically and pharmacodynamically in rats. In multiple-dose experiments, CZ or FZ was given to rats at a daily dose of 20 μmol/kg for 1, 5, 10, 15, and 30 days, and CZ, FZ, and the ring-hydroxylated metabolites of their cinnamyl moiety [1-(diphenylmethyl)-4-[3-(4′-hydroxyphenyl)-2-propenyl] piperazine, C-2 and 1-[bis(4-fluorophenyl)methyl]-4-[3-(4′-hydroxyphenyl)propenyl]piperazine, F-2] in the plasma and striatum were determined 24 hr after the final dose. Plasma and striatum concentrations of the above compounds except for FZ reached steady state after 10 doses, but their concentrations of FZ continued to increase throughout 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 > FZ > CZ > C-2 for the striatum. The ratios of striatum to plasma concentrations 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 for rat striatal dopamine D-2 receptors (D2-R) were assessed by competitive radioligand-binding studies using [3H]-N-[(2RS,3RS)-1-benzyl-2-methyl-3-pyrrolidinyl]-5-chloro-2-methoxy-4-methylamino-benzamide ([3H]-YM-09151-2). The IC50s calculated from their Ki values were in the order of F-2 <C-2 <FZ <CZ <C-4 ≪ F-1, indicating that C-2 and F-2 exhibit higher affinities for D2-R than the parent drugs, whereas affinities of other metabolites were 1 to 2 orders of magnitude less than those of C-2 and F-2. These results 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.
| Original language | English |
|---|---|
| Pages (from-to) | 1645-1650 |
| Number of pages | 6 |
| Journal | Biochemical Pharmacology |
| Volume | 50 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - Nov 9 1995 |
| Externally published | Yes |
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Keywords
- active metabolite
- blood concentration
- cinnarizine
- dopamine D-2 receptor
- flunarizine
- parkinsonism
- striatum
ASJC Scopus subject areas
- Biochemistry
- Pharmacology
Cite this
Possible pharmacokinetic and pharmacodynamic factors affecting parkinsonism inducement by cinnarizine and flunarizine. / Kariya, Satoru; Isozaki, Sadao; Masubuchi, Yasuhiro; Suzuki, Tokuji; Narimatsu, Shizuo.
In: Biochemical Pharmacology, Vol. 50, No. 10, 09.11.1995, p. 1645-1650.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Possible pharmacokinetic and pharmacodynamic factors affecting parkinsonism inducement by cinnarizine and flunarizine
AU - Kariya, Satoru
AU - Isozaki, Sadao
AU - Masubuchi, Yasuhiro
AU - Suzuki, Tokuji
AU - Narimatsu, Shizuo
PY - 1995/11/9
Y1 - 1995/11/9
N2 - Potentialities of cinnarizine [1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine, CZ] and its fluorine derivative flunarizine [1-[bis(4-fluorophenyl)-methyl]-4-(3-phenyl-2-propenyl)piperazine, FZ] to induce parkinsonism as an adverse effect were evaluated pharmacokinetically and pharmacodynamically in rats. In multiple-dose experiments, CZ or FZ was given to rats at a daily dose of 20 μmol/kg for 1, 5, 10, 15, and 30 days, and CZ, FZ, and the ring-hydroxylated metabolites of their cinnamyl moiety [1-(diphenylmethyl)-4-[3-(4′-hydroxyphenyl)-2-propenyl] piperazine, C-2 and 1-[bis(4-fluorophenyl)methyl]-4-[3-(4′-hydroxyphenyl)propenyl]piperazine, F-2] in the plasma and striatum were determined 24 hr after the final dose. Plasma and striatum concentrations of the above compounds except for FZ reached steady state after 10 doses, but their concentrations of FZ continued to increase throughout 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 > FZ > CZ > C-2 for the striatum. The ratios of striatum to plasma concentrations 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 for rat striatal dopamine D-2 receptors (D2-R) were assessed by competitive radioligand-binding studies using [3H]-N-[(2RS,3RS)-1-benzyl-2-methyl-3-pyrrolidinyl]-5-chloro-2-methoxy-4-methylamino-benzamide ([3H]-YM-09151-2). The IC50s calculated from their Ki values were in the order of F-2 <C-2 <FZ <CZ <C-4 ≪ F-1, indicating that C-2 and F-2 exhibit higher affinities for D2-R than the parent drugs, whereas affinities of other metabolites were 1 to 2 orders of magnitude less than those of C-2 and F-2. These results 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.
AB - Potentialities of cinnarizine [1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine, CZ] and its fluorine derivative flunarizine [1-[bis(4-fluorophenyl)-methyl]-4-(3-phenyl-2-propenyl)piperazine, FZ] to induce parkinsonism as an adverse effect were evaluated pharmacokinetically and pharmacodynamically in rats. In multiple-dose experiments, CZ or FZ was given to rats at a daily dose of 20 μmol/kg for 1, 5, 10, 15, and 30 days, and CZ, FZ, and the ring-hydroxylated metabolites of their cinnamyl moiety [1-(diphenylmethyl)-4-[3-(4′-hydroxyphenyl)-2-propenyl] piperazine, C-2 and 1-[bis(4-fluorophenyl)methyl]-4-[3-(4′-hydroxyphenyl)propenyl]piperazine, F-2] in the plasma and striatum were determined 24 hr after the final dose. Plasma and striatum concentrations of the above compounds except for FZ reached steady state after 10 doses, but their concentrations of FZ continued to increase throughout 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 > FZ > CZ > C-2 for the striatum. The ratios of striatum to plasma concentrations 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 for rat striatal dopamine D-2 receptors (D2-R) were assessed by competitive radioligand-binding studies using [3H]-N-[(2RS,3RS)-1-benzyl-2-methyl-3-pyrrolidinyl]-5-chloro-2-methoxy-4-methylamino-benzamide ([3H]-YM-09151-2). The IC50s calculated from their Ki values were in the order of F-2 <C-2 <FZ <CZ <C-4 ≪ F-1, indicating that C-2 and F-2 exhibit higher affinities for D2-R than the parent drugs, whereas affinities of other metabolites were 1 to 2 orders of magnitude less than those of C-2 and F-2. These results 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.
KW - active metabolite
KW - blood concentration
KW - cinnarizine
KW - dopamine D-2 receptor
KW - flunarizine
KW - parkinsonism
KW - striatum
UR - http://www.scopus.com/inward/record.url?scp=0028818567&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0028818567&partnerID=8YFLogxK
U2 - 10.1016/0006-2952(95)02057-8
DO - 10.1016/0006-2952(95)02057-8
M3 - Article
C2 - 7503767
AN - SCOPUS:0028818567
VL - 50
SP - 1645
EP - 1650
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 10
ER -