TY - JOUR

T1 - Development of an LC-MS/MS-based method for quantification and pharmacokinetics study on SCID mice of a dehydroabietylamine-adamantylamine conjugate, a promising inhibitor of the DNA repair enzyme

AU - Okhina, Alina A

AU - Rogachev, Artem D

AU - Kovaleva, Kseniya S

AU - Yarovaya, Olga I

AU - Khotskina, Anna S

AU - Zavyalov, Evgeniy L

AU - Vatsadze, Sergey Z

AU - Pokrovsky, Andrey G

AU - Salakhutdinov, Nariman F

N1 - Acknowledgments: Synthesis of the compounds was supported by the program of Ministry of Science and Higher Education of the Russian Federation No. 1021051703312–0-1.4.1. Analytical part of the study was supported by the Ministry of Science and Higher Education of the Russian Federation, project number FSUS-2020–0035. The studies with animals at the Center for Genetic Resources of Laboratory Animals ICG SB RAS are supported by the budget project (No. FWNR-2022–0023). Copyright © 2023 Elsevier B.V. All rights reserved.

PY - 2023/9/20

Y1 - 2023/9/20

N2 - Earlier, it was found that the agent KS-389, a conjugate of dehydroabietylamine and 1-aminoadamantane, possess inhibiting activity with regard to Tdp1. It this study, LC-MS/MS-based methods of quantification of KS-389 in mice blood and several organs (brain, liver and kidney) were developed and validated. Validation of the methods was performed according to the guidelines of U.S. Food and Drug Administration and European Medicines Agency in terms of selectivity, linearity, accuracy, precision, recovery, matrix effect, stability and carry-over. Dried blood spots (DBS) method was used for blood sample preparation. HPLC separation was performed on a reversed-phase column; the total analysis time was 12 min. Mass spectral detection was performed on a 6500 QTRAP mass spectrometer in multiple reaction monitoring mode. Transitions 463.5→135.1/107.2 and 336.2→332.2/176.2 were scanned for KS-389 and 2,5-bis(4-diethylaminophenyl)-1,3,4-oxadiazole used as the internal standard, respectively. Pharmacokinetics of the compound as well as its distribution in the organs were studied on SCID mice after intraperitoneal administration of the substance at a dose of 5 mg/kg, and it was found that its maximum concentration in blood is reached in 1-1.5 h and was 80 ng/mL. The maximum concentration in all organs is reached after the same time and is approximately 1500 ng/g and 1100 ng/g in liver and kidney, respectively. This is the first report on the pharmacokinetics of Tdp1 inhibitor based on dehydroabietylamine and 1-aminoadamantane after a single administration to mice. Also, the substance was found to be able to penetrate the blood-brain barrier which is important for, and its maximum concentration was c.a. 25-30 ng/g. These results are important for glioma treatment and make it promising for this purpose.

AB - Earlier, it was found that the agent KS-389, a conjugate of dehydroabietylamine and 1-aminoadamantane, possess inhibiting activity with regard to Tdp1. It this study, LC-MS/MS-based methods of quantification of KS-389 in mice blood and several organs (brain, liver and kidney) were developed and validated. Validation of the methods was performed according to the guidelines of U.S. Food and Drug Administration and European Medicines Agency in terms of selectivity, linearity, accuracy, precision, recovery, matrix effect, stability and carry-over. Dried blood spots (DBS) method was used for blood sample preparation. HPLC separation was performed on a reversed-phase column; the total analysis time was 12 min. Mass spectral detection was performed on a 6500 QTRAP mass spectrometer in multiple reaction monitoring mode. Transitions 463.5→135.1/107.2 and 336.2→332.2/176.2 were scanned for KS-389 and 2,5-bis(4-diethylaminophenyl)-1,3,4-oxadiazole used as the internal standard, respectively. Pharmacokinetics of the compound as well as its distribution in the organs were studied on SCID mice after intraperitoneal administration of the substance at a dose of 5 mg/kg, and it was found that its maximum concentration in blood is reached in 1-1.5 h and was 80 ng/mL. The maximum concentration in all organs is reached after the same time and is approximately 1500 ng/g and 1100 ng/g in liver and kidney, respectively. This is the first report on the pharmacokinetics of Tdp1 inhibitor based on dehydroabietylamine and 1-aminoadamantane after a single administration to mice. Also, the substance was found to be able to penetrate the blood-brain barrier which is important for, and its maximum concentration was c.a. 25-30 ng/g. These results are important for glioma treatment and make it promising for this purpose.

KW - Amantadine

KW - Animals

KW - Chromatography, Liquid/methods

KW - DNA Repair Enzymes

KW - Limit of Detection

KW - Mice

KW - Mice, SCID

KW - Reproducibility of Results

KW - Tandem Mass Spectrometry/methods

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85163305435&origin=inward&txGid=85ebffc9c1f0f330bcd07e24fd673fe8

UR - https://www.mendeley.com/catalogue/962226ca-a4e7-305b-83e2-d643d4483f87/

U2 - 10.1016/j.jpba.2023.115507

DO - 10.1016/j.jpba.2023.115507

M3 - Article

C2 - 37331915

VL - 234

JO - Journal of Pharmaceutical and Biomedical Analysis

JF - Journal of Pharmaceutical and Biomedical Analysis

SN - 0731-7085

M1 - 115507

ER -