Paulzen Michael, Haen Ekkehard, Stegmann Benedikt, Hiemke Christoph, Gründer Gerhard, Lammertz Sarah E, Schoretsanitis Georgios
Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, and JARA - Translational Brain Medicine, Pauwelsstraße 30, 52074 Aachen, Germany.
Clinical Pharmacology, Department of Psychiatry and Psychotherapy and Department of Pharmacology and Toxicology, University of Regensburg, Universitätsstrasse 84, 93053 Regensburg, Germany.
Psychoneuroendocrinology. 2016 Nov;73:9-15. doi: 10.1016/j.psyneuen.2016.07.009. Epub 2016 Jul 18.
We sought to unravel the influence of body weight and body mass index (BMI), both consistently reported as pharmacokinetic relevant parameters, on metabolism of risperidone in a naturalistic sample.
Conducting non parametrical tests we sought for correlations between plasma concentrations of RIS, 9-OH-RIS and AM and body weight and BMI in patients out of a therapeutic drug monitoring (TDM) database. Further, we stratified patients to three groups based upon BMI values and compared drug concentrations between groups.
Although body weight failed to correlate with pharmacokinetic parameters, BMI was positively correlated with plasma concentrations of the active metabolite (9-OH-RIS) (r=0.121, p=0.002) and active moiety (sum of RIS+9-OH-RIS) (r=0.128, p=0.001) as well as dose adjusted plasma concentrations of the active moiety (r=0.08, p=0.04). The comparison of pharmacokinetic parameters between different BMI groups yielded lower plasma concentrations of 9-OH-RIS in patients with low BMI (<20kg/m) and higher plasma concentrations of the active moiety in obese patients (BMI ≥30kg/m) when compared with the control group (30>BMI≥20kg/m). By comparing low vs. high BMI patients, the latter group showed higher 9-OH-RIS plasma concentrations.
Considerable alterations in metabolism of risperidone were detected when comparing obese and cachectic patients with the control group in alignment with the positive correlation between BMI values and plasma concentrations of the active metabolite and active moiety as well as dose adjusted plasma concentrations of the active moiety. We suggest changes in CYP2D6 or CYP3A4 activity or differences in P-glycoprotein function in obese patients with greater BMI as a plausible mechanism underlying these alterations.
我们试图揭示体重和体重指数（BMI）这两个一直被报道为与药代动力学相关参数的因素，对自然样本中利培酮代谢的影响。
我们在一个治疗药物监测（TDM）数据库的患者中，通过进行非参数检验来寻找利培酮（RIS）、9-羟基利培酮（9-OH-RIS）和活性代谢物（AM）的血浆浓度与体重和BMI之间的相关性。此外，我们根据BMI值将患者分为三组，并比较各组之间的药物浓度。
尽管体重与药代动力学参数无相关性，但BMI与活性代谢物（9-OH-RIS）的血浆浓度呈正相关（r=0.121，p=0.002），与活性部分（RIS+9-OH-RIS的总和）呈正相关（r=0.128，p=0.001），以及与活性部分的剂量调整血浆浓度呈正相关（r=0.08，p=0.04）。与对照组（30>BMI≥20kg/m²）相比，不同BMI组之间药代动力学参数的比较显示，低BMI（<20kg/m²）患者的9-OH-RIS血浆浓度较低，肥胖患者（BMI≥30kg/m²）的活性部分血浆浓度较高。通过比较低BMI与高BMI患者，后一组显示出更高的9-OH-RIS血浆浓度。
与对照组相比，在肥胖和消瘦患者中检测到利培酮代谢有相当大的改变，这与BMI值与活性代谢物和活性部分的血浆浓度以及活性部分的剂量调整血浆浓度之间的正相关一致。我们认为，BMI较高的肥胖患者中CYP2D6或CYP3A4活性的变化或P-糖蛋白功能的差异是这些改变的一个合理机制。
