TY - JOUR

T1 - Biostability study, quantitation method and preliminary pharmacokinetics of a new antifilovirus agent based on borneol and 3-(piperidin-1-yl)propanoic acid

AU - Rogachev, Artem D.

AU - Putilova, Valentina P.

AU - Zaykovskaya, Anna V.

AU - Yarovaya, Olga I.

AU - Sokolova, Anastasiya S.

AU - Fomenko, Vladislav V.

AU - Pyankov, Oleg V.

AU - Maksyutov, Rinat A.

AU - Pokrovsky, Andrey G.

AU - Salakhutdinov, Nariman F.

N1 - Funding Information: Authors acknowledge the Ministry of Science and Higher Education of the Russian Federation for financial support of the synthetic part (project registration number AAAA-А21-121011490014-4) as well as the analytical part (project FSUS-2020-0035) of this study. Publisher Copyright: © 2021 Elsevier B.V. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/5/30

Y1 - 2021/5/30

N2 - The stability of the new antifiloviral agent AS-358, which is a derivative of borneol and 3-(piperidin-1-yl)propanoic acid, was studied in the blood and blood plasma of rats in vitro. It was found that both in the blood and in the plasma stabilized by EDTA or heparin, the compound is rapidly hydrolyzed at the ester bond. When sodium fluoride was added to the whole blood, the decomposition of the compound was significantly slowed down, which made it possible to develop and validate a method for the quantitative determination of the agent in this matrix. The method was validated in terms of selectivity, calibration dependence, LLOQ, accuracy and precision, stability in an autosampler, recovery, and carry-over. A 8:2 v/v mixture of methanol containing 2-adamantylamine hydrochloride (internal standard, IS) with 0.2 M aqueous zinc sulfate was used for blood sample treatment and protein precipitation. Analysis was performed by HPLC-MS/MS using reversed phase chromatography. MS/MS detection was performed on a triple quadrupole mass spectrometer 6500 QTRAP (SCIEX) in multiple reaction monitoring (MRM) mode. The transitions 294.5→158.2/98.1 and 152.2→107.2/93.1 were monitored for AS-358 and the IS, respectively. The calibration curve was built in the concentration range of 1−500 ng/mL, the intra-day and inter-day accuracy and precision, carry-over and recovery were within the acceptable limits. The developed method was used for a preliminary study of the pharmacokinetics of the agent AS-358 after its oral administration to rats. It was shown that when the substance was administered at a dose of 200 mg/kg, its concentration in the blood of animals reached 550 ng/mL after 1 h, despite its instability in blood.

AB - The stability of the new antifiloviral agent AS-358, which is a derivative of borneol and 3-(piperidin-1-yl)propanoic acid, was studied in the blood and blood plasma of rats in vitro. It was found that both in the blood and in the plasma stabilized by EDTA or heparin, the compound is rapidly hydrolyzed at the ester bond. When sodium fluoride was added to the whole blood, the decomposition of the compound was significantly slowed down, which made it possible to develop and validate a method for the quantitative determination of the agent in this matrix. The method was validated in terms of selectivity, calibration dependence, LLOQ, accuracy and precision, stability in an autosampler, recovery, and carry-over. A 8:2 v/v mixture of methanol containing 2-adamantylamine hydrochloride (internal standard, IS) with 0.2 M aqueous zinc sulfate was used for blood sample treatment and protein precipitation. Analysis was performed by HPLC-MS/MS using reversed phase chromatography. MS/MS detection was performed on a triple quadrupole mass spectrometer 6500 QTRAP (SCIEX) in multiple reaction monitoring (MRM) mode. The transitions 294.5→158.2/98.1 and 152.2→107.2/93.1 were monitored for AS-358 and the IS, respectively. The calibration curve was built in the concentration range of 1−500 ng/mL, the intra-day and inter-day accuracy and precision, carry-over and recovery were within the acceptable limits. The developed method was used for a preliminary study of the pharmacokinetics of the agent AS-358 after its oral administration to rats. It was shown that when the substance was administered at a dose of 200 mg/kg, its concentration in the blood of animals reached 550 ng/mL after 1 h, despite its instability in blood.

KW - Liquid chromatography

KW - Pharmacokinetics

KW - Sample preparation

KW - Sample stability

KW - Tandem mass spectrometry

KW - Validation

KW - Reproducibility of Results

KW - Rats

KW - Camphanes

KW - Chromatography, High Pressure Liquid

KW - Tandem Mass Spectrometry

KW - Animals

KW - Propionates

UR - http://www.scopus.com/inward/record.url?scp=85103973953&partnerID=8YFLogxK

U2 - 10.1016/j.jpba.2021.114062

DO - 10.1016/j.jpba.2021.114062

M3 - Article

C2 - 33862506

AN - SCOPUS:85103973953

VL - 199

JO - Journal of Pharmaceutical and Biomedical Analysis

JF - Journal of Pharmaceutical and Biomedical Analysis

SN - 0731-7085

M1 - 114062

ER -