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Receptor occupancy-based analysis of the contributions of various receptors to antipsychotics-induced weight gain and diabetes mellitus.
Drug Metab Pharmacokinet. 2005 Oct; 20(5):368-78.DM

Abstract

OBJECTIVE

Among various adverse reactions of atypical antipsychotics, weight gain and impaired glucose tolerance are clinically significant. The aim of this study is to analyze quantitatively the contributions of various receptors to these antipsychotics-induced adverse reactions based on the receptor occupancy theory.

METHODS

Two indices of antipsychotics-induced weight gain (the values estimated by a meta-analysis and the observed values in clinical trials) and the morbidity rate of type 2 diabetes mellitus during treatment with antipsychotics were taken from the literature. We calculated the estimated mean receptor occupancies of alpha1 adrenergic, alpha2 adrenergic, dopamine D2, histamine H1, muscarinic acetylcholine (mACh), serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors by antipsychotics by using the pharmacokinetic parameters and receptor dissociation constants, and analyzed the correlation between the occupancies and the extent of adverse reactions as assessed using the aforementioned indices.

RESULTS

There were statistically significant correlations between the estimated occupancies of H1 and mACh receptors and antipsychotics-induced weight gain estimated by meta-analysis (r(s) = 0.81 and r(s) = 0.83, respectively, p < 0.01). There were also statistically significant correlations between these receptor occupancies and observed weight gain in clinical trials (r(s) = 0.66 in each case, p < 0.01). The morbidity rate of type 2 diabetes mellitus was highly correlated with H1, mACh, and 5-HT2C receptor occupancies (r(s) = 0.90 in each case, p < 0.05). However, H1 receptor occupancy was also highly correlated with mACh receptor occupancy among antipsychotics, so that only one of them may be critically associated with the adverse reactions. Considering that these adverse reactions have not been reported for drugs with mACh receptor antagonistic action, other than antipsychotics, the H1 receptor may contribute predominantly to the antipsychotics-induced weight gain and diabetes mellitus.

DISCUSSION/CONCLUSION

Model analysis based on receptor occupancy indicates that H1 receptor blockade is the primary cause of antipsychotics-induced weight gain and diabetes mellitus.

Authors+Show Affiliations

Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16272755

Citation

Matsui-Sakata, Akiko, et al. "Receptor Occupancy-based Analysis of the Contributions of Various Receptors to Antipsychotics-induced Weight Gain and Diabetes Mellitus." Drug Metabolism and Pharmacokinetics, vol. 20, no. 5, 2005, pp. 368-78.
Matsui-Sakata A, Ohtani H, Sawada Y. Receptor occupancy-based analysis of the contributions of various receptors to antipsychotics-induced weight gain and diabetes mellitus. Drug Metab Pharmacokinet. 2005;20(5):368-78.
Matsui-Sakata, A., Ohtani, H., & Sawada, Y. (2005). Receptor occupancy-based analysis of the contributions of various receptors to antipsychotics-induced weight gain and diabetes mellitus. Drug Metabolism and Pharmacokinetics, 20(5), 368-78.
Matsui-Sakata A, Ohtani H, Sawada Y. Receptor Occupancy-based Analysis of the Contributions of Various Receptors to Antipsychotics-induced Weight Gain and Diabetes Mellitus. Drug Metab Pharmacokinet. 2005;20(5):368-78. PubMed PMID: 16272755.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Receptor occupancy-based analysis of the contributions of various receptors to antipsychotics-induced weight gain and diabetes mellitus. AU - Matsui-Sakata,Akiko, AU - Ohtani,Hisakazu, AU - Sawada,Yasufumi, PY - 2005/11/8/pubmed PY - 2006/1/13/medline PY - 2005/11/8/entrez SP - 368 EP - 78 JF - Drug metabolism and pharmacokinetics JO - Drug Metab Pharmacokinet VL - 20 IS - 5 N2 - OBJECTIVE: Among various adverse reactions of atypical antipsychotics, weight gain and impaired glucose tolerance are clinically significant. The aim of this study is to analyze quantitatively the contributions of various receptors to these antipsychotics-induced adverse reactions based on the receptor occupancy theory. METHODS: Two indices of antipsychotics-induced weight gain (the values estimated by a meta-analysis and the observed values in clinical trials) and the morbidity rate of type 2 diabetes mellitus during treatment with antipsychotics were taken from the literature. We calculated the estimated mean receptor occupancies of alpha1 adrenergic, alpha2 adrenergic, dopamine D2, histamine H1, muscarinic acetylcholine (mACh), serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors by antipsychotics by using the pharmacokinetic parameters and receptor dissociation constants, and analyzed the correlation between the occupancies and the extent of adverse reactions as assessed using the aforementioned indices. RESULTS: There were statistically significant correlations between the estimated occupancies of H1 and mACh receptors and antipsychotics-induced weight gain estimated by meta-analysis (r(s) = 0.81 and r(s) = 0.83, respectively, p < 0.01). There were also statistically significant correlations between these receptor occupancies and observed weight gain in clinical trials (r(s) = 0.66 in each case, p < 0.01). The morbidity rate of type 2 diabetes mellitus was highly correlated with H1, mACh, and 5-HT2C receptor occupancies (r(s) = 0.90 in each case, p < 0.05). However, H1 receptor occupancy was also highly correlated with mACh receptor occupancy among antipsychotics, so that only one of them may be critically associated with the adverse reactions. Considering that these adverse reactions have not been reported for drugs with mACh receptor antagonistic action, other than antipsychotics, the H1 receptor may contribute predominantly to the antipsychotics-induced weight gain and diabetes mellitus. DISCUSSION/CONCLUSION: Model analysis based on receptor occupancy indicates that H1 receptor blockade is the primary cause of antipsychotics-induced weight gain and diabetes mellitus. SN - 1347-4367 UR - https://www.unboundmedicine.com/medline/citation/16272755/Receptor_occupancy_based_analysis_of_the_contributions_of_various_receptors_to_antipsychotics_induced_weight_gain_and_diabetes_mellitus_ L2 - http://joi.jlc.jst.go.jp/JST.JSTAGE/dmpk/20.368?from=PubMed DB - PRIME DP - Unbound Medicine ER -