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Pharmaceutics 2018, 10(3), 124; https://doi.org/10.3390/pharmaceutics10030124

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

1
Department of Pharmacology, School of Basic Medical Sciences, Peking University, No.38 Xue-Yuan Road, Beijing 100191, China
2
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
3
Proteomics Laboratory, Medical and Health Analysis Center, Peking University, Beijing 100191, China
4
Department of Drug Metabolism & Pharmacokinetics (DMPK), Sanofi, Waltham, MA 02451, USA
*
Authors to whom correspondence should be addressed.
Received: 29 June 2018 / Revised: 21 July 2018 / Accepted: 27 July 2018 / Published: 8 August 2018
(This article belongs to the Special Issue Preclinical Pharmacokinetics and Bioanalysis)
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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 (Cmax), and the area under the curve (AUC0–∞) were increased by the dose-dependent and linear manner, but the marked different of plasma half-life (t1/2) 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. View Full-Text
Keywords: methyl 3-amino-6-methoxythieno [2,3-b] quinolone-2-carboxylate (PU-48); plasma pharmacokinetics; tissue distribution; excretion; plasma protein binding; rat methyl 3-amino-6-methoxythieno [2,3-b] quinolone-2-carboxylate (PU-48); plasma pharmacokinetics; tissue distribution; excretion; plasma protein binding; rat
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Zhang, Z.-Y.; Zhang, H.; Liu, D.; Lu, Y.-Y.; Wang, X.; Li, P.; Lou, Y.-Q.; Yang, B.-X.; Lou, Y.-X.; Lu, C.; Zhang, Q.; Zhang, G.-L. Pharmacokinetics, Tissue Distribution and Excretion of a Novel Diuretic (PU-48) in Rats. Pharmaceutics 2018, 10, 124.

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