Receptor occupancy-based analysis of the contributions of various receptors to antipsychotics-induced weight gain and diabetes mellitus.
Receptor occupancy-based analysis of the contributions of various receptors to antipsychotics-induced weight gain and diabetes mellitus.
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DOI：
10.2133/dmpk.20.368
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发表时间：
2005-10-01
影响因子：
2.1
通讯作者：
Sawada, Yasufumi
中科院分区：
文献类型：
--
作者：
Matsui-Sakata, Akiko;Ohtani, Hisakazu;Sawada, Yasufumi
目的：在非典型抗精神病药物的各种不良反应中，体重增加和糖耐量降低具有显著的临床意义。本研究的目的是基于受体占位理论，定量分析各种受体在抗精神病药物引起的不良反应中的作用。方法：从文献中获取抗精神病药物治疗期间2型糖尿病患者体重增加的两个指标（meta分析估计值和临床试验观察值）和发病率。利用药代动力学参数和受体解离常数计算抗精神病药物对α 1肾上腺素能、α 2肾上腺素能、多巴胺D2、组胺H1、毒毒碱乙酰胆碱（mACh）、5-HT1A、5-HT2A和5-HT2C受体的估计平均占用率，并分析占用率与不良反应程度的相关性。结果：meta分析估计的H1和mACh受体占用率与抗精神病药物引起的体重增加有统计学意义(r（s) = 0.81和r(s) = 0.83, p < 0.01）。在临床试验中，这些受体占用率与观察到的体重增加之间也存在统计学意义上的相关性（r(s) = 0.66, p < 0.01）。2型糖尿病发病率与H1、mACh、5-HT2C受体占用率高度相关（r(s) = 0.90, p < 0.05）。然而，在抗精神病药物中，H1受体占用率也与mACh受体占用率高度相关，因此只有其中一种可能与不良反应密切相关。考虑到除抗精神病药物外，具有马赫受体拮抗剂作用的药物尚未报道这些不良反应，H1受体可能是抗精神病药物诱导的体重增加和糖尿病的主要原因。讨论/结论：基于受体占用的模型分析表明，H1受体阻断是抗精神病药物引起体重增加和糖尿病的主要原因。
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.