title: Prediction and assessment of extrapyramidal side effects induced by risperidone based on dopamine D(2) receptor occupancy.
abstract: In the present study, we attempted to predict the risk of extrapyramidal side effects of a selective monoaminergic antagonist, risperidone, by analyzing the correlation between the dopamine D(2) receptor occupancy and the degree of extrapyramidal side effects of the drug. The occupancies of D(2) and 5-HT(2) receptors at various doses of risperidone were calculated by means of a receptor occupancy theory. The extrapyramidal side effects after administration of risperidone were attempted to predict by theoretical analysis of the correlation between the calculated occupancies and the evidence of extrapyramidal symptoms using a ternary complex model. The pharmacokinetic/pharmacodynamic analysis utilized the data concerning the pharmacokinetics of risperidone and 9-hydroxyrisperidone (active metabolite), their binding affinities with D(2) and 5-HT(2) receptors, and the clinical evidence of extrapyramidal symptoms (Extrapyramidal Symptom Rating Scale: ESRS), gathered from the literature. The mean occupancy of 5-HT(2) receptors after the administration of regular doses of risperidone was suggested to be more than 90%, whereas the mean occupancy of D(2) receptors varied between 50-80%, depending on the dose. The correlation between the occupancy of D(2) receptors and the extrapyramidal symptoms could be successfully analyzed with a ternary complex model, showing the predictability of the model for the extrapyramidal side effects of risperidone. Since the estimated risk of the extrapyramidal side effects varied with the dose, the present method of predicting the extrapyramidal side effects of risperidone may provide a basis for developing a rational dosing regimen for the drug.
authors.affiliation: Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Hongo, Tokyo, Japan. yamada-tky@umin.ac.jp
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamada
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ohno
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Nakashima
authors.forename: Masato
authors.initials: M
authors.lastname: Fukuda
authors.forename: Risa
authors.initials: R
authors.lastname: Takayanagi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sato
authors.forename: Fumito
authors.initials: F
authors.lastname: Tsuchiya
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Sawada
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Iga
mesh_terms: D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D001480:Basal Ganglia Diseases / Q000139:chemically induced*; D018492:Dopamine Antagonists / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007555:Isoxazoles / Q000009:adverse effects / Q000493:pharmacokinetics; D008954:Models, Biological; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D018967:Risperidone / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D007555:Isoxazoles; D011743:Pyrimidines; D017448:Receptors, Dopamine D2; D018967:Risperidone; D000068882:Paliperidone Palmitate