Pharmacokinetic study of Tdp1 inhibitor resulted in a significant increase in antitumor effect in the treatment of Lewis lung carcinoma in mice by its combination with topotecan

Alina A Okhina; Tatyana E Kornienko; Artem D Rogachev; Olga A Luzina; Nelly A Popova; Valery P Nikolin; Alexandra L Zakharenko; Nadezhda S Dyrkheeva; Andrey G Pokrovsky; Nariman F Salakhutdinov; Olga I Lavrik

doi:10.1016/j.jpba.2023.115731

Pharmacokinetic study of Tdp1 inhibitor resulted in a significant increase in antitumor effect in the treatment of Lewis lung carcinoma in mice by its combination with topotecan

J Pharm Biomed Anal. 2023 Nov 30:236:115731. doi: 10.1016/j.jpba.2023.115731. Epub 2023 Sep 18.

Affiliations

¹ N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry of the Siberian Branch of Russian Academy of Sciences, Lavrent'ev ave., 9, Novosibirsk 630090, Russia; Novosibirsk State University, Pirogov St., 2, Novosibirsk 630090, Russia.
² Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of Russian Academy of Sciences, Lavrent'ev ave., 8, Novosibirsk 630090, Russia.
³ N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry of the Siberian Branch of Russian Academy of Sciences, Lavrent'ev ave., 9, Novosibirsk 630090, Russia.
⁴ Novosibirsk State University, Pirogov St., 2, Novosibirsk 630090, Russia; Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Lavrent'ev ave., 10, Novosibirsk 630090, Russia.
⁵ Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Lavrent'ev ave., 10, Novosibirsk 630090, Russia.
⁶ Novosibirsk State University, Pirogov St., 2, Novosibirsk 630090, Russia.
⁷ Novosibirsk State University, Pirogov St., 2, Novosibirsk 630090, Russia; Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of Russian Academy of Sciences, Lavrent'ev ave., 8, Novosibirsk 630090, Russia. Electronic address: lavrik@niboch.nsc.ru.

PMID: 37741072
DOI: 10.1016/j.jpba.2023.115731

Abstract

We have previously shown that the Tdp1 inhibitor, enamine derivative of usnic acid, the agent OL9-116, enhances the antitumor activity of topotecan. In the present study, we developed and validated LC-MS/MS method for the quantification of OL9-116 in mouse whole blood and studied pharmacokinetics of the agent. The substance OL9-116 was shown to be stable in the whole blood in vitro. Sample preparation included two steps: mixing 10 µL of a blood sample with 10 µL of 0.2 M ZnSO₄ aqueous solution, followed by protein precipitation with 100 µL of acetonitrile containing internal standard. Quantification of the compound was performed using SCIEX 6500 QTRAP mass spectrometer in MRM mode following chromatographic separation on a C8 reversed-phase column. The method was validated in terms of selectivity, linearity, accuracy, precision, recovery, and stability of the prepared sample. When the agent OL9-116 was administered intragastrically at a dose of 150 mg/kg, the maximum concentration in the blood (about 5000 ng/mL) was reached after 2-4 h followed by the distribution and elimination of the compound. A study of the antitumor activity of a combination of OL9-116 and topotecan against Lewis lung carcinoma revealed that administration of topotecan 3 h after OL9-116 resulted in the most pronounced antitumor effect compared to simultaneous or individual administration of both compounds.

Keywords: Antitumor activity; LC-MS/MS; Pharmacokinetics; Topotecan; Tyrosyl DNA phosphodiesterase 1; Usnic acid derivative.