DETERMINATION OF PHARMACOKINETIC PARAMETERS FROM DISTRIBUTION STUDY FOLLOWING DEVELOPMENT AND VALIDATION OF A SENSITIVE LC-MS METHOD IN TISSUE MATRICES FOR 2-(4-ETHOXYPHENYLSULPHONAMIDO) PENTANEDIAMIDE, AN INVESTIGATIONAL ANTICANCER AGENT

N. Yeasmin, Suvasish Mishra, Subrata Sen
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Abstract

Objective: The aim of this study was to develop and validate bioanalytical methods for estimation of 2-(4-ethoxyphenyl sulphamido) pentanediamide (PC), an investigational anticancer agent, in various organ/tissue matrices to study various Pharmacokinetic parameters using lC-MS. Methods: Freshly prepared tissue homogenates from Sprague-Dawley rats were used as matrices to develop the bioanalytical method in lC-MS to determine Cmax, Tmax, AUC0-t, AUC0-inf, T1/2, and mean Residence Time (MRT). The distribution study was conducted by administering PC orally to Sprague-Dawley rats and quantifying PC in different excised organs at different points. A non-compartmental analysis was done using ‘PK solver’ software. Results: In all the tissue matrices, the concentrations of PC were found in the linear range of 10 to 5000 ng/ml. High level of precision, accuracy, and recovery, with negligible matrix effects, were found. PC was distributed in all tissues except the brain. Pharmacokinetic parameters such as Tmax and MRT were between 1.11±0.12 to 2.33±0.11 h and 2.17±0.16 to 4.01±0.25 h respectively in the liver, lung, heart, spleen, kidney, and thymus. Conclusion: Simple and sensitive lC-MS methods for PC in different tissue matrices were developed and validated. As PC does not cross Blood Brain Barrier (BBB), it will not adversely affect Central Nervous System (CNS). PC is absorbed fast from Gastro Intestinal Tract (GIT) to blood and subsequently reaches the different tissues. Consequently, a fast onset of action will be seen. To sum up, PC is a probable potential anticancer agent with no or minimal adverse effects on CNS.
在组织基质中开发和验证灵敏的 2-(4-乙氧基苯磺酰胺基)戊二酰胺(一种在研抗癌剂)lc-ms 方法后,通过分布研究确定药代动力学参数
研究目的本研究旨在开发和验证生物分析方法,利用 lC-MS 在各种器官/组织基质中估算 2-(4-乙氧基苯基氨基磺酰基)戊二酰胺(PC)这种在研抗癌剂的药代动力学参数:以 Sprague-Dawley 大鼠新鲜制备的组织匀浆为基质,开发 lC-MS 生物分析方法,测定 Cmax、Tmax、AUC0-t、AUC0-inf、T1/2 和平均停留时间(MRT)。分布研究是通过给 Sprague-Dawley 大鼠口服多氯联苯,并在不同时间点对不同切除器官中的多氯联苯进行定量。使用 "PK solver "软件进行了非室分析:在所有组织基质中,PC 的浓度均在 10 至 5000 纳克/毫升的线性范围内。该方法的精密度、准确度和回收率都很高,基质效应可忽略不计。除大脑外,PC 在所有组织中都有分布。在肝、肺、心、脾、肾和胸腺中的药代动力学参数,如 Tmax 和 MRT 分别为 1.11±0.12 至 2.33±0.11 h 和 2.17±0.16 至 4.01±0.25 h:本文建立并验证了不同组织基质中 PC 的简便灵敏的 lC-MS 方法。由于多氯联苯不会穿过血脑屏障(BBB),因此不会对中枢神经系统(CNS)产生不利影响。PC 从胃肠道(GIT)到血液的吸收速度很快,随后会到达不同的组织。因此,起效速度很快。总之,多氯化萘可能是一种对中枢神经系统无不良影响或不良影响极小的潜在抗癌剂。
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