Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa city, Iowa (N.W., G.A.); Department of Entomology and Nematology and UCD Cancer Research Center, University of California at Davis, Davis, California (B.D.H.); and Departments of Pharmacology and Toxicology and Chemistry, Michigan State University, East Lansing, Michigan (K.S.S.L.).
Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa city, Iowa (N.W., G.A.); Department of Entomology and Nematology and UCD Cancer Research Center, University of California at Davis, Davis, California (B.D.H.); and Departments of Pharmacology and Toxicology and Chemistry, Michigan State University, East Lansing, Michigan (K.S.S.L.)
J Pharmacol Exp Ther. 2020 Jul;374(1):223-232. doi: 10.1124/jpet.120.265330. Epub 2020 Apr 1.
1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU) and 1-(4-trifluoro-methoxy-phenyl)-3-(1-cyclopropanecarbonyl-piperidin-4-yl)-urea (TCPU) are potent inhibitors of soluble epoxide hydrolase (sEH) that have much better efficacy in relieving nociceptive response than the Food and Drug Administration-approved drug gabapentin in a rodent model of diabetic neuropathy. Experiments conducted in sEH knockout mice or with coadministration of a potent sEH displacer demonstrated that the pharmacokinetics of TPPU and TCPU were influenced by the specific binding to their pharmacologic target sEH, a phenomenon known as target-mediated drug disposition (TMDD). To quantitatively characterize the complex pharmacokinetics of TPPU and TCPU and gain better understanding on their target occupancy, population pharmacokinetics analysis using a nonlinear mixed-effect modeling approach was performed in the current study. The final model was a novel simultaneous TMDD interaction model, in which TPPU and TCPU compete for sEH, with TCPU binding to an additional unknown target pool with larger capacity that we refer to as a refractory pool. The total amount of sEH enzyme in mice was predicted to be 16.2 nmol, which is consistent with the experimental value of 10 nmol. The dissociate rate constants of TPPU and TCPU were predicted to be 2.24 and 2.67 hours, respectively, which is close to the values obtained from in vitro experiments. Our simulation result predicted that 90% of the sEH will be occupied shortly after a low dose of 0.3 mg/kg TPPU administration, with ≥40% of sEH remaining to be bound with TPPU for at least 7 days. Further efficacy experiments are warranted to confirm the predicted target occupancy. SIGNIFICANCE STATEMENT: Although target-mediated drug disposition (TMDD) models have been well documented, most of them were established in a single compound scenario. Our novel model represents the first TMDD interaction model for two small-molecule compounds competing for the same pharmacological target.
1-(1-丙酰基哌啶-4-基)-3-[4-(三氟甲氧基)苯基]脲（TPPU）和 1-(4-三氟甲氧基苯基）-3-(1-环丙烷羰基-哌啶-4-基）-脲（TCPU）是可溶性环氧化物水解酶（sEH）的有效抑制剂，在糖尿病神经病变的啮齿动物模型中，它们在缓解伤害性反应方面的疗效比美国食品和药物管理局批准的药物加巴喷丁要好得多。在 sEH 敲除小鼠中进行的实验或与强效 sEH 置换剂共同给药表明，TPPU 和 TCPU 的药代动力学受其药理靶标 sEH 的特异性结合影响，这种现象称为靶介导的药物处置（TMDD）。为了定量描述 TPPU 和 TCPU 的复杂药代动力学并更好地了解其靶标占有率，本研究采用非线性混合效应建模方法进行了群体药代动力学分析。最终模型是一种新颖的同时 TMDD 相互作用模型，其中 TPPU 和 TCPU 竞争 sEH，TCPU 与我们称为难治性池的具有更大容量的额外未知靶标池结合。预测小鼠中 sEH 酶的总量为 16.2 nmol，与实验值 10 nmol 一致。预测 TPPU 和 TCPU 的解离速率常数分别为 2.24 和 2.67 小时，与体外实验获得的值接近。我们的模拟结果预测，在低剂量 0.3 mg/kg TPPU 给药后不久，将有 90%的 sEH 被占据，至少 7 天内仍有≥40%的 sEH 与 TPPU 结合。需要进一步的疗效实验来证实预测的靶标占有率。意义陈述：尽管已经很好地记录了靶介导的药物处置（TMDD）模型，但它们中的大多数都是在单个化合物的情况下建立的。我们的新型模型代表了第一个用于两种小分子化合物竞争相同药理靶标的 TMDD 相互作用模型。
