Urinary Excretion of Nadolol as a Possible In Vivo Probe for Drug Interactions Involving P‐Glycoprotein
Urinary Excretion of Nadolol as a Possible In Vivo Probe for Drug Interactions Involving P‐Glycoprotein
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纳多洛尔的尿排泄作为涉及 P-糖蛋白的药物相互作用的可能体内探针
DOI：
10.1002/jcph.1812
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Misaka Shingen
中科院分区：
文献类型：
--
作者：
Shimazaki Sho;Kuroda Junko;Shimomura Kenju;Misaka Shingen
纳多洛尔是一种亲水性非选择性β-肾上腺素受体阻滞剂，生物利用度为30%，半衰期相对较长，代谢可忽略不计，主要通过肾脏排泄。先前的研究报道纳多洛尔是P-糖蛋白的底物，与典型的P-糖蛋白抑制剂伊曲康唑合用会导致纳多洛尔的血浆浓度和尿累积排泄升高。在这项研究中，我们评估了尿排泄纳多洛尔的测量是否可以作为人体 P-糖蛋白介导的药物相互作用的血浆药代动力学的替代方法。我们重新分析了之前对 32 名健康日本成年人进行的临床研究中纳多洛尔血浆浓度和尿液排泄的汇总数据集。个体受试者中纳多洛尔从0到无穷大的血浆浓度-时间曲线下面积（AUC0-∞）与最大血浆浓度（r= 0.80，P<.01）和4（r= 0.51，P= .01）、8（r= 0.63，P< .01）、24（r= 0.75，P< .01) 和 48 (r= 0.77，P< .01) 小时。同一时期的 AUC 和 Aed 之间也观察到显着相关性。在纳多洛尔与伊曲康唑、利福平（一种著名的 P-糖蛋白诱导剂）或柚子汁的药物相互作用中，个体受试者中 AUC0-48 和 Ae, 0-48 的差异之间存在显着相关性。这些结果表明，纳多洛尔尿排泄的测量可以作为血浆药代动力学的敏感且可靠的替代方案，用于评估 P-糖蛋白介导的药物相互作用。
Nadolol is a hydrophilic and nonselective β‐adrenoceptor blocker with a bioavailability of 30%, relatively longer half‐life, negligible metabolism, and predominant renal excretion. Previous studies have reported that nadolol is a substrate of P‐glycoprotein, and the coadministration with itraconazole, a typical P‐glycoprotein inhibitor, results in elevated plasma concentrations and cumulative urinary excretion of nadolol. In this study, we assessed whether measurements of urinary‐excreted nadolol can be an alternative method of plasma pharmacokinetics for P‐glycoprotein‐mediated drug interactions in humans. We reanalyzed the pooled data set of plasma concentration and urinary excretion of nadolol from our previous clinical studies in a total of 32 healthy Japanese adults. The area under the plasma concentration‐time curve from 0 to infinity (AUC0‐∞) of nadolol in individual subjects was significantly correlated with the maximum plasma concentration (r= 0.80,P< .01) and the cumulative amount excreted into urine (Ae) at 4 (r= 0.51,P= .01), 8 (r= 0.63,P< .01), 24 (r= 0.75,P< .01), and 48 (r= 0.77,P< .01) hours. Significant correlations were also observed between the AUC andAeduring the same respective periods. In the drug interactions of nadolol with itraconazole, rifampicin, a well‐known P‐glycoprotein inducer, or grapefruit juice, there were significant correlations between the differences in AUC0‐48and those inAe, 0‐48from the controls in individual subjects. These results suggest that the measurements of urinary excretion of nadolol can be employed as a sensitive and reliable alternative to plasma pharmacokinetics for the evaluation of P‐glycoprotein‐mediated drug interactions.
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