Study of fabomotizole belonging to p-glycoprotein substrates

Abstract

P-glycoprotein (Pgp) is a membrane efflux protein transporter with numerous drug-substrates. In addition, a lot of drugs alter the activity of the transporter. It can lead to drug-drug interactions during polypharmacy. Fabomotizole (afobazol) is a Russian anxiolytic drug with neuroprotective activity, applied over a wide range of indications. The drug belongs to a potential substrate of Pgp according to its chemical structure.

Aim. The aim of the study was to assess belonging of fabomotizole to Pgp substrates.

Materials and Methods. The work was performed on 12 male Chinchilla rabbits. The belonging of fabomotizole to Pgp substrates was evaluated by comparing pharmacokinetic parameters of the test-substance after course administration of known transporter inducers and inhibitors – rifampicin and verapamil respectively. Fabomotizole was administered orally as a single dose of 3.8 mg/kg b.w. and blood was taken from the ear vein after 5, 10, 15, 20, 30, 60, 90, 120 and 240 min followed by it's pharmacokinetic analysis by HPLC. Pharmacokinetic parameters of fabomotizole were manually calculated by a model-independent method. The animals were then divided into 2 groups of 6 rabbits each: the 1st group received verapamil at a dose 20 mg/kg b.w. 3 times a day for 14 days, the 2nd – rifampicin in a similar course and dose. After the administration of Pgp modulators the pharmacokinetics of fabomotizole were re-analyzed.

Results. It was found that only the absorption coefficient of fabomotizole in the rifampicin series was significantly reduced by 1.27 times as compared to the parameter of intact animals (90% CI 0.66-0.94, p=0.04322). However, this change was not clinically significant, because 90% CI overlapped the range of 0.80-1.25, noted by FDA. The remaining pharmacokinetic parameters of Pgp marker substrate were not significantly changed in any series. This is evidence that fabomotizole is not a Pgp substrate. The insignificant participation of Pgp in fabomotizole pharmacokinetics testifies that the drug can be administered together with drug-modulators of transporter activity without dose correction.

Conclusion. In vivo experiment on Chinchilla rabbits showed that fabomotizole is not a substrate of P-glycoprotein.

Keywords

P-glycoprotein / fabomotizole / pharmacokinetics / rifampicin / verapamil / substrate

References

[1] 1.Montanari F, Ecker GF. Prediction of drug-ABC-transporter interaction – recent advances and future challenges. Advanced Drug Delivery Reviews. 2015;86:17-26.

[2] 1.Montanari F., Ecker G.F. Prediction of drug-ABC-transporter interaction – Recent advances and future challenges // Advanced Drug Delivery Reviews. 2015. Vol. 86. P. 17-26.

[3] 2.Avedisova AS. Afobazol – bezopasnyy preparat dlya lecheniya trevogi v obshchey praktike. Russkiy meditsinskiy zhurnal. 2006;14(22):1-3. (In Russ).

[4] 2.Аведисова А.С. Афобазол – безопасный препарат для лечения тревоги в общей практике // Русский медицинский журнал. 2006. Т. 14, №22. С. 1-3.

[5] 3.Ecker G, Huber M, Schmid D, et al. The importance of a nitrogen atom in modulators of multidrug resistance. Molecular Pharmacology. 1999;56(4):791-6.

[6] 3.Ecker G., Huber M., Schmid D., et al. The importance of a nitrogen atom in modulators of multidrug resistance // Molecular Pharmacology. 1999. Vol. 56, №4. P. 791-796.

[7] 4.El-Ela AA, Härtter S, Schmitt U, et al. Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds-implications for pharmacokinetics of selected substrates. Journal of Pharmacy and Pharmacology. 2004;56(8):967-75.

[8] 4.El-Ela A.A., Härtter S., Schmitt U., et al. Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds-implications for pharmacokinetics of selected substrates // Journal of Pharmacy and Pharmacology. 2004. Vol. 56, №8. P. 967-975.

[9] 5.Kaletina NI. Toksikologicheskaya khimiya metabolizm i analiz toksikantov. Moscow: GEOTAR-MEDIA; 2008. (in Russ)

[10] 5.Калетина Н.И. Токсикологическая химия метаболизм и анализ токсикантов. М.: ГЭОТАР-МЕДИА; 2008.

[11] 6.Gatsanoga MV, Chernykh IV, Shchulkin AV, et al. Mozhno li otsenivat' prinadlezhnost' lekarstvennykh veshchestv k substratam glikoproteina-P na samkakh krolikov porody shinshilla? Nauka molodykh (Eruditio Juvenium). 2016;4(3):5-10. (In Russ).

[12] 6.Гацанога М.В., Черных И.В., Щулькин А.В., и др. Можно ли оценивать принадлежность лекарственных веществ к субстратам гликопротеина-P на самках кроликов породы шиншилла // Наука молодых (Eruditio Juvenium). 2016. Т. 4, №3. С. 5-10.

[13] 7.Yakusheva EN, Shchulkin AV, Chernykh IV. Ocenka prinadlezhnosti meksi-dola k substratam, i ingibitoram ili indukto-ram glikoproteina-R. Eksperimental'naya i klinicheskaya farmakologiya. 2015;78(5):19-23. (In Russ).

[14] 7.Якушева Е.Н., Щулькин А.В., Черных И.В. Оценка принадлежности мексидола к субстратам, и ингибиторам или индукторам гликопротеина-Р // Экспериментальная и клиническая фармакология. 2015. Т. 78, №5. С. 19-23.

[15] 8.Khubriev RU. Rukovodstvo po eksperimental'nomu (doklinicheskomu) izu-cheniyu novykh farmakologicheskikh veshchestv. Moscow: Medicina; 2005. (In Russ).

[16] 8.Хабриев Р.У. Руководство по экспериментальному (доклиническому) изучению новых фармакологических веществ. М.: ОАО Издательство «Медицина»; 2005.

[17] 9.Gribakina OG, Kolyvanov GB, Litvin AA, et al. Farmakokineticheskoye vzaimodeystviye afobazola s lozartanom – preparatom-substratom tsitokhroma CYP2C9 v eksperimente. Eksperimental'naya i klini-cheskaya farmakologiya. 2013;76(3):35-7. (In Russ).

[18] 9.Грибакина О.Г., Колыванов Г.Б., Литвин А.А., и др. Фармакокинетическое взаимодействие афобазола с лозартаном – препаратом-субстратом цитохрома CYP2C9 в эксперименте // Экспериментальная и клиническая фармакология. 2013. Т. 76, №3. С. 35-37.

[19] 10.Yakusheva EN, Chernykh IV, Shchulkin AV, et al. Metodika opredeleniya prinadlezhnosti lekarstvennykh sredstv k chislu substratov glikoproteina-P. Rossijskiy mediko-biologicheskiy vestnik imeni akademika I.P. Pavlova. 2015;23(3):49-53. (In Russ).

[20] 10.Якушева Е.Н., Черных И.В., Щулькин А.В., и др. Методика определения принадлежности лекарственных средств к числу субстратов гликопротеина-P // Российский медико-биологический вестник имени академика И.П. Павлова. 2015. Т. 23, №3. С. 49-53.

[21] 11.Bamberger DM, Fields MT, Herndon BL. Efficacies of various antimicrobial agents in treatment of Staphylococcus aureus abscesses and correlation with in vitro tests of antimicrobial activity and neutrophil killing. Antimicrobial Agents and Chemotherapy. 1991;35(11):2335-9.

[22] 11.Bamberger D.M., Fields M.T., Herndon B.L. Efficacies of various antimicrobial agents in treatment of Staphylococcus aureus abscesses and correlation with in vitro tests of antimicrobial activity and neutrophil killing // Antimicrobial Agents and Chemotherapy. 1991. Vol. 35, №11. P. 2335-2339.

[23] 12.Nare B, Liu Z, Prichard RK, et al. Benzimidazoles – potent anti-mitotic drugs: substrates for the P-glycoprotein transporter in multidrug-resistant cells. Biochemical pharmacology. 1994;48(12):2215-22.

[24] 12.Nare B., Liu Z., Prichard R.K., et al. Benzimidazoles – potent anti-mitotic drugs: substrates for the P-glycoprotein transporter in multidrug-resistant cells // Bioche-mical pharmacology. 1994. Vol. 48, №12. P. 2215-2222.

[25] 13.Seredenin SB, Voronin MV. Farmakologiya novogo anksiolitika afoba-zola. Eksperimental'naya i klinicheskaya farmakologiya. 2009;72(1):3-11. (In Russ).

[26] 13.Середенин С.Б., Воронин М.В. Фармакология нового анксиолитика афобазола // Экспериментальная и клиническая фармакология. 2009. Т. 72, №1. С. 3-11.

[27] 14.Cuevas J, Behensky A, Deng W, et al. Afobazole Modulates Neuronal Response to Ischemia and Acidosis via Activation of σ-1 Receptors. Journal of pharmacology and experimental therapeutics. 2011;339(1):152-60.

[28] 14.Cuevas J., Behensky A., Deng W., et al. Afobazole Modulates Neuronal Response to Ischemia and Acidosis via Activation of σ-1 Receptors // Journal of pharmacology and experimental therapeutics. 2011. Vol. 339, №1. P. 152-160.

RIGHTS & PERMISSIONS

Chernykh I.V., Shchulkin A.V., Yakusheva E.N., Gatsanoga M.V., Popova N.v.