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

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.

SUBMITTER: Zhang ZY

PROVIDER: S-EPMC6160999 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimTolsultazolamide, a novel carbonic anhydrase inhibitor, is designed for the prophylaxis and treatment of acute mountain sickness. The aim of this study was to investigate the pharmacokinetics, tissue distribution, and excretion characteristics of tolsultazolamide and the sex difference in pharmacokinetics in rats.MethodsFor pharmacokinetic study, rats were intravenously injected tolsultazolamide at 1 and 2 mg/kg or orally administered tolsultazolamide at 20, 40, or 80 mg/kg) in a pharmacokinetic study. The concentrations of tolsultazolamide in plasma were determined with high-performance liquid chromatography, with a liquid-liquid extraction. For tissue distribution study, tolsultazolamide (80 mg/kg) was orally administered to overnight fasted rats (six per group and three per sex). Samples were collected from the brain, heart, lung, liver, spleen, muscle, kidney, stomach, fat, intestines, pancreas and sexual gland. For excretion study, tolsultazolamide (40 mg/kg) was orally administered to 6 rats (three per sex). The urine, feces, and bile samples were collected at 24, 48, and 72 h.ResultsAfter its intravenous administration, tolsultazolamide was rapidly eliminated from the plasma, with T1/2 of about 60-90 min. The AUC0-t and the initial concentration (C0) values were proportional to the intravenous doses. After its oral administration, tolsultazolamide showed dose-independent pharmacokinetic characteristics, with Tmax and T1/2 of approximately 2 h and 5-7 h, respectively, and good oral absolute bioavailability of about 60%. Tolsultazolamide was distributed widely in various tissues. The highest tolsultazolamide levels were detected in the stomach, intestine, spleen, lung, and kidney. Total excretion of unchanged tolsultazolamide in the urine, feces, and bile was less than 2%. The Cmax and AUC of tolsultazolamide were significantly higher in female rats than those in male rats. Clearance and volume of distribution were greater in male rats than those in female rats. The oral absolute bioavailability was also significantly different between female rats (about 83%) and male rats (about 37%).ConclusionTolsultazolamide was well absorbed and widely distributed in the rat, and very little of the unchanged form was excreted. Sex had a significant effect on the pharmacokinetics of tolsultazolamide.

Project description:PPI-1011 is a synthetic plasmalogen precursor in development as a treatment for multiple plasmalogen-deficiency disorders. Previous work has demonstrated the ability of PPI-1011 to augment plasmalogens and its effects in vitro and in vivo, however, the precise uptake and distribution across tissues in vivo has not been investigated. The purpose of this study was to evaluate the pharmacokinetics, mass balance, and excretion of [14C]PPI-1011 following a single oral administration at 100 mg/kg in Sprague-Dawley rats. Further tissue distribution was examined using quantitative whole-body autoradiography after both single and repeat daily doses at 100 mg/kg/day. Non-compartmental analysis showed that following a single dose, PPI-1011 exhibited peak levels between 6 and 12 h but also a long half-life with mean t1/2 of 40 h. Mass balance showed that over 50% of the compound-associated radioactivity was absorbed by the body, while approximately 40% was excreted in the feces, 2.5% in the urine, and 10% in expired air within the first 24 h. Quantitative whole-body autoradiography following a single dose showed uptake to nearly all tissues, with the greatest initial uptake in the intestines, liver, and adipose tissue, which decreased time-dependently throughout 168 h post-dose. Following 15 consecutive daily doses, uptake was significantly higher across the entire body at 24 h compared to single dose and remained high out to 96 h where 75% of the initially-absorbed compound-associated radioactivity was still present. The adipose tissue remained particularly high, suggesting a possible reserve of either plasmalogens or alkyl diacylglycerols that the body can pull from for plasmalogen biosynthesis. Uptake to the brain was also definitively confirmed, proving PPI-1011's ability to cross the blood-brain barrier. In conclusion, our results suggest that oral administration of PPI-1011 results in high uptake across the body, and that repeated dosing over time represents a viable therapeutic strategy for treating plasmalogen deficiencies.

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

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