当前位置: X-MOL 学术Anim. Cells Syst. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Pharmacokinetic, metabolic stability, plasma protein binding and CYP450s inhibition/induction assessment studies of N-(2-pyridylmethyl)-2-hydroxiymethyl-1-pyrrolidinyl-4-(3-chloro-4-methoxy-benzylamino)-5-pyrimidine-carboxamide as potential type 5 phosphodiesterase inhibitors
Animal Cells and Systems ( IF 2.5 ) Pub Date : 2019-05-04 , DOI: 10.1080/19768354.2019.1614091
Haijun Qu 1 , Xiaoxiao Hu 1 , Xiaoli Shi 1 , Chuan Wang 1 , Longyuan Wang 1 , Guoping Wang 1
Affiliation  

ABSTRACT N-(2-pyridylmethyl)-2-hydroxiymethyl-1-pyrrolidinyl-4-(3-chloro-4-methoxy-benzylamino)-5-pyrimidine-carboxamide (NHPPC) is a new potential of type 5 phosphodiesterase (PDE5) inhibitors, synthesized from the avanafil analogue for the treatment of erectile dysfunction. The targets of this article were to assess plasma protein binding, liver microsomal metabolic stability, inhibition and induction on cytochrome P450 isozymes and the pharmacokinetics of NHPPC. Equilibrium dialysis technique was applied to determine Plasma protein binding (PPB) and NHPPC was evaluated in male Sprague–Dawley rats and Beagle dogs in vivo pharmacokinetic. The NHPPC was highly bound to plasma proteins in rats, dogs and human tested and the mean values for PPB rate were 96.2%, 99.6% and 99.4%, respectively. After in vitro liver microsomes incubated for 60 min, the percent remaining of NHPPC was 42.8%, 0.8% and 42.0% in rats, dogs and human, respectively. In vitro intrinsic clearance was found to be 0.0233, 0.1204 and 0.0214 mL/min/mg protein in rat, dog and human liver microsomes of NHPPC, respectively. NHPPC showed no significant inhibitory effects on major CYP450 enzymes, and had no significant induction potential on CYP1A2 and CYP3A4. Following oral administration in rats and dogs, tmax was 6 and 0.5 h, respectively. The clearance for NHPPC was 1.19 and 1.46 L/h/kg in rats and dogs, respectively. And absolute bioavailability in rat and dog were approximately 34.5% and 53.1%, respectively. These results showed that NHPPC has a good development prospect.

中文翻译:

N-(2-pyridylmethyl)-2-hydroxymethyl-1-pyrrolidinyl-4-(3-chloro-4-methoxy-benzylamino)-5-pyrimidine-的药代动力学、代谢稳定性、血浆蛋白结合和 CYP450s 抑制/诱导评估研究甲酰胺作为潜在的 5 型磷酸二酯酶抑制剂

摘要 N-(2-pyridylmethyl)-2-hydroxiymethyl-1-pyrrolidinyl-4-(3-chloro-4-methoxy-benzylamino)-5-pyrimidine-carboxamide (NHPPC) 是一种新的潜力 5 型磷酸二酯酶 (PDE5)抑制剂,由阿伐那非类似物合成,用于治疗勃起功能障碍。本文的目标是评估血浆蛋白结合、肝微粒体代谢稳定性、对细胞色素 P450 同工酶的抑制和诱导以及 NHPPC 的药代动力学。平衡透析技术用于测定血浆蛋白结合 (PPB),并在雄性 Sprague-Dawley 大鼠和 Beagle 犬体内药代动力学中评估 NHPPC。NHPPC 与大鼠、狗和人体的血浆蛋白高度结合,PPB 率的平均值分别为 96.2%、99.6% 和 99.4%。体外肝微粒体孵育 60 min 后,NHPPC 的剩余百分比在大鼠、狗和人中分别为 42.8%、0.8% 和 42.0%。发现 NHPPC 的大鼠、狗和人肝微粒体的体外内在清除率分别为 0.0233、0.1204 和 0.0214 mL/min/mg 蛋白质。NHPPC 对主要 CYP450 酶无显着抑制作用,对 CYP1A2 和 CYP3A4 无显着诱导潜力。在大鼠和狗中口服给药后,tmax 分别为 6 和 0.5 小时。NHPPC 在大鼠和狗中的清除率分别为 1.19 和 1.46 L/h/kg。大鼠和狗的绝对生物利用度分别约为 34.5% 和 53.1%。这些结果表明NHPPC具有良好的发展前景。NHPPC 在大鼠、狗和人肝微粒体中分别为 1204 和 0.0214 mL/min/mg 蛋白质。NHPPC 对主要 CYP450 酶无显着抑制作用,对 CYP1A2 和 CYP3A4 无显着诱导潜力。在大鼠和狗中口服给药后,tmax 分别为 6 和 0.5 小时。NHPPC 在大鼠和狗中的清除率分别为 1.19 和 1.46 L/h/kg。大鼠和狗的绝对生物利用度分别约为 34.5% 和 53.1%。这些结果表明NHPPC具有良好的发展前景。NHPPC 在大鼠、狗和人肝微粒体中分别为 1204 和 0.0214 mL/min/mg 蛋白质。NHPPC 对主要 CYP450 酶无显着抑制作用,对 CYP1A2 和 CYP3A4 无显着诱导潜力。在大鼠和狗中口服给药后,tmax 分别为 6 和 0.5 小时。NHPPC 在大鼠和狗中的清除率分别为 1.19 和 1.46 L/h/kg。大鼠和狗的绝对生物利用度分别约为 34.5% 和 53.1%。这些结果表明NHPPC具有良好的发展前景。分别。NHPPC 在大鼠和狗中的清除率分别为 1.19 和 1.46 L/h/kg。大鼠和狗的绝对生物利用度分别约为 34.5% 和 53.1%。这些结果表明NHPPC具有良好的发展前景。分别。NHPPC 在大鼠和狗中的清除率分别为 1.19 和 1.46 L/h/kg。大鼠和狗的绝对生物利用度分别约为 34.5% 和 53.1%。这些结果表明NHPPC具有良好的发展前景。
更新日期:2019-05-04
down
wechat
bug