Gravel Sophie, Chiasson Jean-Louis, Dallaire Suzanne, Turgeon Jacques, Michaud Veronique
Faculty of Pharmacy, Université de Montréal, Montreal, Canada.
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Canada.
BMJ Open. 2018 Feb 8;8(2):e020922. doi: 10.1136/bmjopen-2017-020922.
Diabetes affects more than 9% of the adult population worldwide. Patients with type 2 diabetes mellitus (T2DM) show variable responses to some drugs which may be due, in part, to variability in the functional activity of drug-metabolising enzymes including cytochromes P450 (CYP450s). CYP450 is a superfamily of enzymes responsible for xenobiotic metabolism. Knowledge must be gained on the impact of T2DM and related inflammatory processes on drug metabolism and its consequences on drug response. The aim of this study is to characterise the activity of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in T2DM versus non-T2DM subjects following the administration of a cocktail of probe drug substrates.
This single-centre clinical study proposes the first detailed characterisation of T2DM impacts on major CYP450 drug-metabolising enzyme activities. We intend to recruit 42 patients with controlled T2DM (A1C≤7%), 42 patients with uncontrolled T2DM (A1C>7%) and 42 non-diabetic control subjects. The primary objective is to determine and compare major CYP450 activities in patients with T2DM versus non-diabetic subjects by dosing in plasma and urine probe drug substrates and metabolites following the oral administration of a drug cocktail: caffeine (CYP1A2), bupropion (CYP2B6), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4/5). Secondary objectives will evaluate the influence of variables such as glycaemia, insulinaemia, genetic polymorphisms and inflammation. The value of an endogenous biomarker of CYP3A activity is also evaluated. The first patient was recruited in May 2015 and patients will be enrolled up to completion of study groups.
Approval was obtained from the ethic review board of the CHUM research centre (Montreal, Canada).
NCT02291666.
糖尿病影响着全球超过9%的成年人口。2型糖尿病（T2DM）患者对某些药物表现出不同的反应，这可能部分归因于包括细胞色素P450（CYP450s）在内的药物代谢酶功能活性的变异性。CYP450是负责外源性物质代谢的酶超家族。必须了解T2DM及相关炎症过程对药物代谢的影响及其对药物反应的后果。本研究的目的是在给予探针药物底物混合物后，对T2DM患者与非T2DM患者中CYP1A2、CYP2B6、CYP2C9、CYP2C19、CYP2D6、CYP2E1和CYP3A4/5的活性进行表征。
这项单中心临床研究首次详细表征了T2DM对主要CYP450药物代谢酶活性的影响。我们打算招募42名T2DM控制良好（糖化血红蛋白≤7%）的患者、42名T2DM控制不佳（糖化血红蛋白>7%）的患者和42名非糖尿病对照受试者。主要目标是通过口服药物混合物后测定血浆和尿液中的探针药物底物及代谢物，来确定并比较T2DM患者与非糖尿病受试者的主要CYP450活性：咖啡因（CYP1A2）、安非他酮（CYP2B6）、甲苯磺丁脲（CYP2C9）、奥美拉唑（CYP2C19）、右美沙芬（CYP2D6）、氯唑沙宗（CYP2E1）和咪达唑仑（CYP3A4/5）。次要目标将评估血糖、胰岛素血症、基因多态性和炎症等变量的影响。还将评估CYP3A活性内源性生物标志物的价值。第一名患者于2015年5月招募，患者将持续入组直至研究组完成。
获得了CHUM研究中心（加拿大蒙特利尔）伦理审查委员会的批准。
NCT02291666。
