Pharmacokinetics, Tissue Distribution and Excretion of a Novel Diuretic (PU-48) in Rats

Zhi-Yuan Zhang; Hua Zhang; Dan Liu; Ying-Yuan Lu; Xin Wang; Pu Li; Ya-Qing Lou; Bao-Xue Yang; Ya-Xin Lou; Chuang Lu; Qiang Zhang; Guo-Liang Zhang

doi:10.3390/pharmaceutics10030124

Pharmacokinetics, Tissue Distribution and Excretion of a Novel Diuretic (PU-48) in Rats

Pharmaceutics. 2018 Aug 8;10(3):124. doi: 10.3390/pharmaceutics10030124.

Authors

Zhi-Yuan Zhang¹, Hua Zhang², Dan Liu³, Ying-Yuan Lu⁴, Xin Wang⁵, Pu Li⁶, Ya-Qing Lou⁷, Bao-Xue Yang⁸, Ya-Xin Lou⁹, Chuang Lu¹⁰, Qiang Zhang¹¹, Guo-Liang Zhang¹²

Affiliations

¹ Department of Pharmacology, School of Basic Medical Sciences, Peking University, No.38 Xue-Yuan Road, Beijing 100191, China. zzy_705@163.com.
² Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. zhangpharm@bjmu.edu.cn.
³ Proteomics Laboratory, Medical and Health Analysis Center, Peking University, Beijing 100191, China. liudan@bjmu.edu.cn.
⁴ Department of Pharmacology, School of Basic Medical Sciences, Peking University, No.38 Xue-Yuan Road, Beijing 100191, China. Luyingyuan2005@126.com.
⁵ Department of Pharmacology, School of Basic Medical Sciences, Peking University, No.38 Xue-Yuan Road, Beijing 100191, China. wangxinpku@bjmu.edu.cn.
⁶ Department of Pharmacology, School of Basic Medical Sciences, Peking University, No.38 Xue-Yuan Road, Beijing 100191, China. lipu9909@126.com.
⁷ Department of Pharmacology, School of Basic Medical Sciences, Peking University, No.38 Xue-Yuan Road, Beijing 100191, China. cdcdname@21cn.com.
⁸ Department of Pharmacology, School of Basic Medical Sciences, Peking University, No.38 Xue-Yuan Road, Beijing 100191, China. baoxue@bjmu.edu.cn.
⁹ Proteomics Laboratory, Medical and Health Analysis Center, Peking University, Beijing 100191, China. louyx@bjmu.edu.cn.
¹⁰ Department of Drug Metabolism & Pharmacokinetics (DMPK), Sanofi, Waltham, MA 02451, USA. chuanglu7@gmail.com.
¹¹ Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. ZQDODO@bjmu.edu.cn.
¹² Department of Pharmacology, School of Basic Medical Sciences, Peking University, No.38 Xue-Yuan Road, Beijing 100191, China. ZhangGL168@bjmu.edu.cn.

Abstract

Methyl 3-amino-6-methoxythieno [2,3-b] quinoline-2-carboxylate (PU-48) is a novel diuretic urea transporter inhibitor. The aim of this study is to investigate the profile of plasma pharmacokinetics, tissue distribution, and excretion by oral dosing of PU-48 in rats. Concentrations of PU-48 within biological samples are determined using a validated high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. After oral administration of PU-48 (3, 6, and 12 mg/kg, respectively) in self-nanomicroemulsifying drug delivery system (SNEDDS) formulation, the peak plasma concentrations (C_max), and the area under the curve (AUC_0⁻∞) were increased by the dose-dependent and linear manner, but the marked different of plasma half-life (t_1/2) were not observed. This suggests that the pharmacokinetic profile of PU-48 prototype was first-order elimination kinetic characteristics within the oral three doses range in rat plasma. Moreover, the prototype of PU-48 was rapidly and extensively distributed into thirteen tissues, especially higher concentrations were detected in stomach, intestine, liver, kidney, and bladder. The total accumulative excretion of PU-48 in the urine, feces, and bile was less than 2%. This research is the first report on disposition via oral administration of PU-48 in rats, and it provides important information for further development of PU-48 as a diuretic drug candidate.

Keywords: excretion; methyl 3-amino-6-methoxythieno [2,3-b] quinolone-2-carboxylate (PU-48); plasma pharmacokinetics; plasma protein binding; rat; tissue distribution.