Candesartan Has No Clinically Meaningful Effect on the Plasma Concentrations of Cytochrome P450 2C8 Substrate Repaglinide in Humans.

IF 4.4 3区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Metabolism and Disposition Pub Date : 2024-11-15 DOI:10.1124/dmd.124.001798
Mikael O W Piha, Kristiina Cajanus, Marica T Engström, Mikko Neuvonen, Troels K Bergmann, Mikko Niemi, Janne T Backman, Anne M Filppula, Aleksi Tornio
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Abstract

In vitro evidence shows that the acyl-β-D-glucuronide metabolite of candesartan inhibits cytochrome P450 (CYP) 2C8 with an inhibition constant of 7.12 μM. 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-β-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 [P = 0.809; 90% confidence interval (CI) 0.90-1.15] and 1.13 (P = 0.346; 90% CI 0.90-1.43), respectively. Other pharmacokinetic variables and blood glucose concentrations were neither affected. Candesartan acyl-β-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 (P = 0.041; 90% CI 1.07-1.62). Systemic concentrations of candesartan acyl-β-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-β-D-glucuronide has been shown to inhibit CYP2C8 in vitro, it shows no clinically relevant CYP2C8 inhibition in humans due to low systemic concentrations.

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坎地沙坦对人体 CYP2C8 底物瑞格列奈的血浆浓度没有临床意义上的影响
体外证据显示,坎地沙坦的酰基-β-D-葡萄糖醛酸代谢物对细胞色素 P450 (CYP) 2C8 有抑制作用,抑制常数为 7.12 µM。我们研究了坎地沙坦对敏感的临床 CYP2C8 指数底物瑞格列奈的血浆浓度和降糖效果的影响。在一项随机交叉研究中,10 名健康志愿者连续 3 天每天摄入 8 毫克坎地沙坦或安慰剂,在第 3 天,他们还在摄入坎地沙坦或安慰剂 1 小时后摄入 0.25 毫克瑞格列奈。我们测量了瑞格列奈、坎地沙坦和坎地沙坦酰-β-D-葡萄糖醛酸的血浆浓度,以及摄入瑞格列奈后长达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浓度峰值没有影响,几何平均比分别为 1.02 [P = 0.809; 90% 置信区间 (CI) 0.90-1.15] 和 1.13 (P = 0.346; 90% CI 0.90-1.43)。其他药代动力学变量和血糖浓度均未受到影响。在 7 名受试者中检测到了坎地沙坦酰-β-D-葡萄糖醛酸,其中瑞格列奈在坎地沙坦阶段的峰值浓度是安慰剂阶段的 1.32 倍(P = 0.041;90% CI 1.07-1.62)。与坎地沙坦酰基-β-D-葡萄糖醛酸的CYP2C8抑制常数相比,坎地沙坦酰基-β-D-葡萄糖醛酸的全身浓度非常低(比值 意义声明 本研究结果表明,坎地沙坦不太可能通过抑制CYP2C8引起药物间相互作用。尽管坎地沙坦酰基-β-D-葡萄糖醛酸已在体外被证明可抑制 CYP2C8,但由于其全身浓度较低,因此在人体中未显示出与临床相关的 CYP2C8 抑制作用。
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来源期刊
CiteScore
6.50
自引率
12.80%
发文量
128
审稿时长
3 months
期刊介绍: An important reference for all pharmacology and toxicology departments, DMD is also a valuable resource for medicinal chemists involved in drug design and biochemists with an interest in drug metabolism, expression of drug metabolizing enzymes, and regulation of drug metabolizing enzyme gene expression. Articles provide experimental results from in vitro and in vivo systems that bring you significant and original information on metabolism and disposition of endogenous and exogenous compounds, including pharmacologic agents and environmental chemicals.
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