Possible pharmacokinetic and pharmacodynamic factors affecting parkinsonism inducement by cinnarizine and flunarizine

Satoru Kariya, Sadao Isozaki, Yasuhiro Masubuchi, Tokuji Suzuki, Shizuo Narimatsu

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 languageEnglish
Pages (from-to)1645-1650
Number of pages6
JournalBiochemical Pharmacology
Volume50
Issue number10
DOIs
Publication statusPublished - Nov 9 1995
Externally publishedYes

Fingerprint

Cinnarizine
Pharmacodynamics
Flunarizine
Pharmacokinetics
Parkinsonian Disorders
Metabolites
Plasmas
Rats
Drug Receptors
Corpus Striatum
Competitive Binding
Fluorine
Pharmaceutical Preparations
Dopamine
Experiments
Derivatives

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 journalArticle

Kariya, Satoru ; Isozaki, Sadao ; Masubuchi, Yasuhiro ; Suzuki, Tokuji ; Narimatsu, Shizuo. / Possible pharmacokinetic and pharmacodynamic factors affecting parkinsonism inducement by cinnarizine and flunarizine. In: Biochemical Pharmacology. 1995 ; Vol. 50, No. 10. pp. 1645-1650.
@article{c11e5d4fae594995836d5ba66c5d3980,
title = "Possible pharmacokinetic and pharmacodynamic factors affecting parkinsonism inducement by cinnarizine and flunarizine",
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.",
keywords = "active metabolite, blood concentration, cinnarizine, dopamine D-2 receptor, flunarizine, parkinsonism, striatum",
author = "Satoru Kariya and Sadao Isozaki and Yasuhiro Masubuchi and Tokuji Suzuki and Shizuo Narimatsu",
year = "1995",
month = "11",
day = "9",
doi = "10.1016/0006-2952(95)02057-8",
language = "English",
volume = "50",
pages = "1645--1650",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "10",

}

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 -