Abstract

1. We evaluated the in vitro drug–drug interaction (DDI) potential of enerisant (TS-091), a histamine H₃ receptor antagonist/inverse agonist, mediated by cytochrome P450 (CYP) and transporters, as well as the pharmacokinetics of enerisant in healthy male subjects.

2. Enerisant did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 and did not induce CYP1A2, CYP2B6, or CYP3A4. Enerisant inhibited organic cation transporter 2, multidrug and toxin extrusion protein (MATE) 1, and MATE2-K, but not P-glycoprotein (P-gp), breast cancer resistance protein, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, or OAT3. Enerisant was a substrate for P-gp, but not for eight other transporters.

3. In healthy male subjects, enerisant was rapidly absorbed after oral administration, and the plasma concentration increased dose-dependently. The urinary excretion of enerisant within 48 h after administration was 64.5% to 89.9% of the dose, indicating that most of the absorbed enerisant was excreted in the urine without being metabolized.

4. Based on the plasma concentrations at the estimated clinical dose, enerisant is unlikely to cause CYP-mediated, clinically relevant DDI. Although the possibility of transporter-mediated, clinically relevant DDI cannot be ruled out, there is little or no risk of side effects.

摘要

1. 我们评估了enerisant (TS-091) 的体外药物相互作用 (DDI) 潜力，一种组胺 H ₃受体拮抗剂/反向激动剂，由细胞色素 P450 (CYP) 和转运蛋白介导，以及 enerisant 在健康人群中的药代动力学。男性科目。

2. Enerisant 不抑制 CYP1A2、CYP2A6、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6、CYP2E1 或 CYP3A4，并且不诱导 CYP1A2、CYP2B6 或 CYP3A4。Enerisant 抑制有机阳离子转运蛋白 2、多药和毒素挤出蛋白 (MATE) 1 和 MATE2-K，但不抑制 P-糖蛋白 (P-gp)、乳腺癌抗性蛋白、有机阴离子转运多肽 (OATP) 1B1、OATP1B3、有机阴离子转运蛋白 (OAT) 1 或 OAT3。Enerisant 是 P-gp 的底物，但不是其他八种转运蛋白的底物。

3. 在健康男性受试者中，能量剂口服后吸收迅速，血浆浓度呈剂量依赖性增加。给药后48 h内增效剂尿排泄量为给药剂量的64.5%～89.9%，表明吸收的增效剂大部分经尿排泄而未代谢。

4. 根据估计临床剂量的血浆浓度，enerisant 不太可能引起 CYP 介导的、临床相关的 DDI。尽管不能排除转运蛋白介导的临床相关 DDI 的可能性，但副作用风险很小或没有。