Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland (M.O.W.P., K.C., A.T.); Bioanalytical Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland (M.T.E.); Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland (M.O.W.P., K.C., A.T.); Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland (M.Ne., M.Ni., J.T.B.); Department of Regional Health Research, University of Southern Denmark, Esbjerg, Denmark and Department of Clinical Pharmacology, Odense University Hospital, Odense, Denmark (T.K.B.); Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (M.Ni., J.T.B.); and Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland (A.M.F.).
Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland (M.O.W.P., K.C., A.T.); Bioanalytical Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland (M.T.E.); Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland (M.O.W.P., K.C., A.T.); Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland (M.Ne., M.Ni., J.T.B.); Department of Regional Health Research, University of Southern Denmark, Esbjerg, Denmark and Department of Clinical Pharmacology, Odense University Hospital, Odense, Denmark (T.K.B.); Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (M.Ni., J.T.B.); and Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland (A.M.F.)
Drug Metab Dispos. 2024 Nov 15;52(12):1388-1395. doi: 10.1124/dmd.124.001798.
In vitro evidence shows that the acyl--D-glucuronide metabolite of candesartan inhibits cytochrome P450 (CYP) 2C8 with an inhibition constant of 7.12 M. We investigated the effect of candesartan on the plasma concentrations and glucose-lowering effect of repaglinide, a sensitive clinical CYP2C8 index substrate. In a randomized crossover study, ten healthy volunteers ingested 8 mg of candesartan or placebo daily for three days, and on day 3, they also ingested 0.25 mg of repaglinide one hour after candesartan or placebo. We measured the plasma concentrations of repaglinide, candesartan, and candesartan acyl--D-glucuronide, and blood glucose concentrations for up to nine hours after repaglinide intake. Candesartan had no effect on the area under the plasma concentration-time curve and peak plasma concentration of repaglinide compared with placebo, with ratios of geometric means of 1.02 [ = 0.809; 90% confidence interval (CI) 0.90-1.15] and 1.13 ( = 0.346; 90% CI 0.90-1.43), respectively. Other pharmacokinetic variables and blood glucose concentrations were neither affected. Candesartan acyl--D-glucuronide was detectable in seven subjects, in whom the peak concentration of repaglinide was 1.32-fold higher in the candesartan phase than in the placebo phase ( = 0.041; 90% CI 1.07-1.62). Systemic concentrations of candesartan acyl--D-glucuronide were very low compared with its CYP2C8 inhibition constant (ratio ≪ 0.1). Furthermore, in a cohort of 93 cancer patients, no indication of decreased paclitaxel clearance was found in four patients using candesartan concomitantly. In conclusion, candesartan therapy is unlikely to inhibit CYP2C8-mediated metabolism of other drugs to any clinically significant extent. SIGNIFICANCE STATEMENT: The findings of this study suggest that candesartan is unlikely to cause drug-drug interactions via inhibition of cytochrome P450 (CYP) 2C8. Although candesartan acyl--D-glucuronide has been shown to inhibit CYP2C8 in vitro, it shows no clinically relevant CYP2C8 inhibition in humans due to low systemic concentrations.
在体外研究中，坎地沙坦的酰基-D-葡萄糖醛酸代谢物对细胞色素 P450（CYP）2C8 的抑制常数为 7.12 μM。我们研究了坎地沙坦对瑞格列奈（一种敏感的临床 CYP2C8 指数底物）的血浆浓度和降血糖作用的影响。在一项随机交叉研究中，10 名健康志愿者连续 3 天每天服用 8mg 坎地沙坦或安慰剂，在第 3 天，他们在服用坎地沙坦或安慰剂 1 小时后也服用 0.25mg 瑞格列奈。我们测量了瑞格列奈、坎地沙坦和坎地沙坦酰基-D-葡萄糖醛酸的血浆浓度以及瑞格列奈摄入后长达 9 小时的血糖浓度。与安慰剂相比，坎地沙坦对瑞格列奈的血浆浓度-时间曲线下面积和血浆峰浓度没有影响，几何均数比值分别为 1.02（=0.809；90%置信区间（CI）0.90-1.15）和 1.13（=0.346；90%CI 0.90-1.43）。其他药代动力学变量和血糖浓度也不受影响。在 7 名受试者中检测到坎地沙坦酰基-D-葡萄糖醛酸，坎地沙坦组的瑞格列奈峰浓度比安慰剂组高 1.32 倍（=0.041；90%CI 1.07-1.62）。与 CYP2C8 抑制常数相比，坎地沙坦酰基-D-葡萄糖醛酸的全身浓度非常低（比值≪0.1）。此外，在 93 名癌症患者的队列中，在 4 名同时使用坎地沙坦的患者中，未发现紫杉醇清除率降低的迹象。总之，坎地沙坦治疗不太可能以任何临床显著的程度抑制 CYP2C8 介导的其他药物的代谢。 意义：这项研究的结果表明，坎地沙坦不太可能通过抑制细胞色素 P450（CYP）2C8 引起药物相互作用。尽管坎地沙坦酰基-D-葡萄糖醛酸在体外已显示出对 CYP2C8 的抑制作用，但由于其全身浓度较低，在人体中没有表现出临床相关的 CYP2C8 抑制作用。
