References

rpcardio

Rational Pharmacotherapy in Cardiology

Рациональная Фармакотерапия в Кардиологии

1819-64462225-3653

«SILICEA-POLIGRAF» LLC

10.20996/1819-6446-2021-01-04

rpcardio-2400

Research Article

CURRENT QUESTIONS OF CLINICAL PHARMACOLOGY

АКТУАЛЬНЫЕ ВОПРОСЫ КЛИНИЧЕСКОЙ ФАРМАКОЛОГИИ

Pharmacokinetics and Pharmacogenetics of Dabigatran

Фармакокинетика и фармакогенетика дабигатрана

https://orcid.org/0000-0002-7036-5326

Савинова

А. В.

Savinova

A. V.

Савинова Алина Валерьевна

Санкт-Петербург

eLibrary SPIN: 4202-7599

Alina V. Savinova

Saint Petersburg

eLibrary SPIN: 4202-7599

https://orcid.org/0000-0002-1367-1669

Добродеева

В. С.

Dobrodeeva

V. S.

Добродеева Вера Сергеевна

Санкт-Петербург

eLibrary SPIN: 3924-3369

Vera S. Dobrodeeva

Saint Petersburg

eLibrary SPIN: 3924-3369

https://orcid.org/0000-0002-8493-0058

Петрова

М. М.

Petrova

M. M.

Петрова Марина Михайловна

Красноярск

eLibrary SPIN: 3531-2179

Marina M. Petrova

Krasnoyarsk

eLibrary SPIN: 3531-2179

https://orcid.org/0000-0003-1874-9434

Насырова

Р. Ф.

Nasyrova

R. F.

Насырова Регина Фаритовна

Санкт-Петербург, Казань

eLibrary SPIN: 3799-0099

Regina F. Nasyrova

Saint Petersburg, Kazan

eLibrary SPIN: 3799-0099

https://orcid.org/0000-0002-2840-837X

Шнайдер

Н. А.

Shnayder

N. A.

Шнайдер Наталья Алексеевна

Санкт-Петербург, Красноярск

eLibrary SPIN: 6517-0279

Natalia A. Shnayder

Saint Petersburg, Krasnoyarsk

eLibrary SPIN: 6517-0279

naschnaider@yandex.ru

Национальный медицинский исследовательский центр психиатрии и неврологии им. В.М. БехтереваРоссияBekhterev National Medical Research Center of Psychiatry and NeurologyRussian Federation

Красноярский государственный медицинский университет им. проф. В.Ф. Войно-ЯсенецкогоРоссияVoyno-Yasenetsky Krasnoyarsk State Medical UniversityRussian Federation

Национальный медицинский исследовательский центр психиатрии и неврологии им. В.М. Бехтерева; Казанский федеральный университетРоссияBekhterev National Medical Research Center of Psychiatry and Neurology; Kazan Federal UniversityRussian Federation

Национальный медицинский исследовательский центр психиатрии и неврологии им. В.М. Бехтерева; Красноярский государственный медицинский университет им. проф. В.Ф. Войно-ЯсенецкогоРоссияBekhterev National Medical Research Center of Psychiatry and Neurology; Voyno-Yasenetsky Krasnoyarsk State Medical UniversityRussian Federation

2021

03032021

171146152

2021

Савинова А.В., Добродеева В.С., Петрова М.М., Насырова Р.Ф., Шнайдер Н.А.

Savinova A.V., Dobrodeeva V.S., Petrova M.M., Nasyrova R.F., Shnayder N.A.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.rpcardio.online/jour/article/view/2400

Dabigatran etexilate is a prodrug of dabigatran, a oral direct inhibitor of thrombin. Pharmacokinetics of dabigatran etexilate doesn’t have the disadvantages of vitamin K antagonists. However, pharmacokinetics and pharmacogenetics of dabigatran are variable. This can affect both effectiveness and safety of anticoagulant therapy. It is considered that CES1 enzyme and P-glycoprotein (CES1 and ABCB1 genes accordingly) play important role in pharmacokinetics of dabigatran etexilate. UDP-glucuronosyltransferase enzymes UGT2B15, UGT1A9, UGT2B7 (UGT2B15, UGT1A9, UGT2B7 genes accordingly) take part in the metabolism of active dabigatran. Presence of these gene’s single-nucleotide variants (SNV) can affect effectiveness and safety of dabigatran etexilate usage. The goal of this review is analysis of associated researches of SNV genes CES1 and ABCB1 and search for new candidate genes that reveal effectiveness and safety of dabigatran etexilate usage.

Materials and methods. The search for full-text publications in Russian and English languages containing key words “dabigatran etexilate”, “dabigatran”, “pharmacokinetics”, “effectiveness”, “safety” was carried out amongst literature of the past twenty years with the use of eLibrary, PubMed, Web of Science, OMIM data bases. Pharmacokinetics and pharmacogenetics of dabigatran etexilate are considered in this review. The hypothesis about UDP-glucuronosyltransferase enzymes influence on dabigatran metabolism was examined. Nowadays more than 2000 SNV CES1 and ABCB1 genes are identified, but their potential influence on pharmacokinetics of dabigatran etexilate and its active metabolite (dabigatran) in clinical practice needs to be further researched. Role of SNV UDP-glucuronosyltransferase genes (UGT2B15, UGT1A9, UGT2B7) in dabigatran’s effectiveness and safety is not explored enough. However, UGT2B15 gene can be a potential candidate gene for research on safety of this drug.

Дабигатрана этексилат – оральный обратимый прямой ингибитор тромбина, который быстро всасывается и превращается в его активную форму – дабигатран. Дабигатран, обладая предсказуемым фармакокинетическим профилем, лишен недостатков, свойственных антагонистам витамина К, но фармакокинетика и фармакогенетика дабигатрана вариабельна, и это может влиять на эффективность и безопасность антикоагулянтной терапии. К настоящему времени показано, что фермент CES1 и P-гликопротеин, кодируемые генами CES1 и ABCB1, оказывают большое влияние на фармакокинетику дабигатрана этексилата. В метаболизме активного дабигатрана участвуют ферменты глюкуронизации UGT2B15, UGT1A9, UGT2B7, кодируемые соответствующими генами (UGT2B15, UGT1A9, UGT2B7). Носительство однонуклеотидных вариантов (ОНВ) этих генов может влиять на эффективность и безопасность применения дабигатрана этексилата. Целью данного обзора является анализ ассоциативных исследований ОНВ генов CES1 и ABCB1, а также поиск новых генов-кандидатов, отражающих эффективность и безопасность применения дабигатрана.

дабигатрана этексилатдабигатранфармакокинетикафармакогенетикаэффективностьбезопасностьCES1ABCB1UGT2B15

dabigatran etexilatedabigatranpharmacokineticseffectivenesssafetyCES1ABCB1UGT2B15

References1

Heit J.A. Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost. 2005; 3(8):1611-7. DOI:10.1111/j.1538-7836.2005.01415.x.

Feigin V.L., Lawes C.M., Bennett D.A., et al. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009; 8(4):355-69. DOI:10.1016/S1474-4422(09)70025-0.

Falck-Ytter Y., Francis C.W., Johanson N.A, et al. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e278S. DOI:10.1378/chest.11-2404.

Pedersen A.B., Mehnert F., Sorensen H.T., et al. The risk of venous thromboembolism, myocardial infarction, stroke, major bleeding and death in patients undergoing total hip and knee replacement. Bone Joint J. 2014;96:479-4805. DOI:10.1302/0301-620x.96b4.33209.

Ageno W., Gallus A.S., Wittkowsky A., et al. Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2):44-88. DOI:10.1378/chest.11-2292.

Ezekowitz M.D., Bridgers S.L., James K.E., et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med. 1992;327(20):1406-12. DOI:10.1056/NEJM199211123272002.

Simonneau G., Sors H., Charbonnier B., et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l'Embolie Pulmonaire. N Engl J Med. 1997;337(10):663-9. DOI:10.1056/NEJM199709043371002.

Holford N.H. Clinical pharmacokinetics and pharmacodynamics of warfarin. Understanding the doseeffect relationship. Clin Pharmacokinet. 1986;11(6):483-504. DOI:10.2165/00003088-198611060-00005.

Shendre A., Parmar G.M., Dillon C., et al. Influence of Age on Warfarin Dose, Anticoagulation Control, and Risk of Hemorrhage. Pharmacotherapy. 2018;38(6):588-96. DOI:10.1002/phar.2089.

Shatzel J.J., Daughety M.M., Prasad V., DeLoughery T.G. Reversal of warfarin era thinking. J Intern Med. 2018;283(4):408-10. DOI:10.1111/joim.12697.

Barnes G.D. Predicting the Quality of Warfarin Therapy: Reframing the Question. Thromb Haemost. 2019;119(4):509-11. DOI:10.1055/s-0039-1681060.

Wu A.H. Pharmacogenomic-guided dosing for warfarin: too little too late? Per Med. 2018;15(2):71- 3. DOI:10.2217/pme-2017-0080.

Schulman S., Kearon C., Kakkar A.K., et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-52. DOI:10.1056/NEJMoa0906598.

Stangier J., Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost. 2009;15(1):9-16. DOI:10.1177/1076029609343004.

Drugs.com. FDA Approves Pradaxa [cited by Jun 15, 2020]. Available from: www.drugs.com/newdrugs/fda-approves-pradaxa-prevent-stroke-atrial-fibrillation-2370.html.

Drugs.com. FDA Approves Pradaxa for deep venous thrombosis and pulmonary embolism [cited by Jun 15, 2020]. Available from: www.drugs.com/newdrugs/fda-approves-pradaxa-deep-venousthrombosis-pulmonary-embolism-4030.html.

Drugs.com. FDA Approves Pradaxa for prophylaxis of deep venous thrombosis and pulmonary embolism after hip replacement surgery [cited by Jun 15, 2020]. Available from: www.drugs.com/newdrugs/fda-approves-pradaxa-prophylaxis-deep-venous-thrombosis-pulmonary-embolism-after-hip-replacement-4304.html.

Stangier J., Rathgen K., Stähle H., et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292-303. DOI:10.1111/j.1365-2125.2007.02899.x.

Hankey G.J., Eikelboom J.W. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation. 2011;123(13):1436-50. DOI:10.1161/CIRCULATIONAHA.110.004424.

Goldsack N.R., Chambers R.C., Dabbagh K., Laurent G.J. Thrombin. Int J Biochem Cell Biol. 1998;30(6):641-6. DOI:10.1016/s1357-2725(98)00011-9.

Davie E.W., Kulman J.D. An overview of the structure and function of thrombin. Semin Thromb Hemost. 2006;32(1):3-15. DOI:10.1055/s-2006-939550.

Comin J., Kallmes D.F. Dabigatran (Pradaxa). American Journal of Neuroradiology. 2002;33(3):426- 8. DOI:10.3174/ajnr.a3000.

Gelosa P., Castiglioni L., Tenconi M., et al. Pharmacokinetic drug interactions of the non-vitamin K antagonist oralanticoagulants (NOACs). Pharmacol Res. 2018;135:60-79. DOI:10.1016/j.phrs.2018.07.016.

Comuth W.J., Henriksen L.Ø., van de Kerkhof D., et al. Comprehensive characteristics of the anticoagulant activity of dabigatran in relation to its plasma concentration. Thromb Res. 2018;164:32- 39. DOI:10.1016/j.thromres.2018.02.141.

Antonijevic N.M., Zivkovic I.D., Jovanovic L.M., et al. Dabigatran - metabolism, pharmacologic properties and drug interactions. Curr Drug Metab. 2017;18(7):622-35. DOI:10.2174/1389200218666170427113504.

Fawzy A.M., Lip G.Y.H. Pharmacokinetics and pharmacodynamics of oral anticoagulants used in atrial fibrillation. Expert Opin Drug Metab Toxicol. 2019;15(5):381-98. DOI:10.1080/17425255.2019.1604686.

Инструкция по медицинскому применению лекарственного препарата Прадакса® 150 мг. Регистрационное удостоверение: ЛП-000872 от 21.10.2016 [цитировано 20.10.2020]. Доступно на: http://grls.rosminzdrav.ru/grls.aspx?s=прадакса&m=tn

Instructions for medical use of Pradaxa® 150 mg. Registration certificate LP-000872 dated 10/21/16 [cited 20.10.2020]. Available from: http://grls.rosminzdrav.ru/grls.aspx?s=прадакса&m=tn (In Russ.)

Bouhajib M., Tayab Z. A Pharmacokinetic evaluation of Dabigatran etexilate, total dabigatran, and unconjugated Dabigatran following the administration of Dabigatran etexilate mesylate capsulesin healthy male and female subjects. Drug Res (Stuttg). 2020;70(1):33-40. DOI:10.1055/a-1025-0119.

Dimatteo C., D'Andrea G., Vecchione G., et al. Pharmacogenetics of dabigatran etexilate interindividual variability. Thromb Res. 2016;144:1-5. DOI:10.1016/j.thromres.2016.05.025.

Satoh T., Hosokawa M. Structure, function and regulation of carboxylesterases. Chem Biol Interact. 2006;162(3):195-211. DOI:10.1016/j.cbi.2006.07.001.

Ghosh S., Natarajan R. Cloning of the human cholesteryl ester hydrolase promoter: identification of functional peroxisomal proliferator-activated receptor responsive elements. Biochem Biophys Res Commun. 2001;284(4):1065-70. DOI:10.1006/bbrc.2001.5078.

Shi J., Wang X., Nguyen J.H., et al. Dabigatran etexilate activation is affected by the CES1 genetic polymorphism G143E (rs71647871) and gender. Biochem Pharmacol. 2016;119:76-84. DOI:10.1016/j.bcp.2016.09.003.

Chen Z., Shi T., Zhang L., et al. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016;370(1):153-64. DOI:10.1016/j.canlet.2015.10.010.

Gouin-Thibault I., Delavenne X., Blanchard A., et al. Interindividual variability in dabigatran and rivaroxaban exposure: contribution of ABCB1 genetic polymorphisms and interaction with clarithromycin. J Thromb Haemost. 2017;15(2):273-283. DOI:10.1111/jth.13577.

Aszalos A. Drug-drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1) I. Preclinical aspects. Drug Discov Today. 2007;12(19-20):833-7. DOI:10.1016/j.drudis.2007.07.022.

Ebner T., Wagner K., Wienen W. Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos. 2010;38(9):1567-75. DOI:10.1124/dmd.110.033696.

UniProt. UDP-glucuronosyltransferase 2B15. UniProt Knowledgebase [cited by Jun 15, 2020]. Available from: www.uniprot.org/uniprot/P54855.

Chung J.Y., Cho J.Y., Yu K.S., et al. Effect of the UGT2B15 genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous lorazepam in healthy volunteers. Clin Pharmacol Ther. 2005;77(6):486‐494. DOI:10.1016/j.clpt.2005.02.006.

Bernier M., Lancrerot S.L., Rocher F., et al. Major bleeding events in octagenarians associated with drug interactions between dabigatran and P-gp inhibitors. J Geriatr Cardiol. 2019;16(11):806-11. DOI:10.11909/j.issn.1671-5411.2019.11.002.

Connolly S.J., Ezekowitz M.D., Yusuf S., et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51. DOI:10.1056/NEJMoa0905561.

Daud A.N., Bergman J.E., Bakker M.K., et al. P-Glycoprotein-mediated drug interactions in pregnancy and changes in the risk of congenital anomalies: a case-reference study. Drug Saf. 2015;38(7):651- 9. DOI:10.1007/s40264-015-0299-3.

Paré G., Eriksson N., Lehr T., et al. Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation. 2013;127(13):1404-12. DOI:10.1161/CIRCULATIONAHA.

Dimatteo C., D'Andrea G., Vecchione G., et al. Pharmacogenetics of dabigatran etexilate interindividual variability. Thromb Res. 2016;144:1-5. DOI:10.1016/j.thromres.2016.05.025.

Сычев Д.А., Абдуллаев Ш.П., Мирзаев К.Б., и др. Генетические детерминанаты безопасности применения прямого ингибитора тромбина среди этнических групп Российской Федерации. Биомедицина. 2019; (1):78-94. DOI:10.33647/2074-5982-15-1-78-94.

Sychev D.A., Abdullaev S.P., Mirzayev K.B., et al. Genetic determinants of the safety of dabigatran (ces1 gene rs2244613 polymorphism) for the Russian population: a multi-ethnic analysis. Journal Biomed. 2019;(1):78-94 (In Russ.) DOI:10.33647/2074-5982-15-1-78-94.

Сычев Д.А., Леванов А.Н., Шелехова Т.В., Шелехова Т.В., и др. Влияние полиморфизма генов abcb1 и ces1 на уровни равновесных концентраций дабигатрана у пациентов после эндопротезирования коленного сустава. Атеротромбоз. 2018;(1):122-30. DOI:10.21518/2307-1109-2018-1-122-130.

Sychev D.A., Levanov A.N., Shelehova T.V., et al. Impact of abcb1 and ces1 genetic polymorphisms on trough steady-state dabigatran concentrations in patients after endoprosthesis of knife join. Atherothrombosis. 2018;(1):122-30 (In Russ.) DOI:10.21518/2307-1109-2018-1-122-130.

He X., Hesse L.M., Hazarika S., et al. Evidence for oxazepam as an in vivo probe of UGT2B15: oxazepam clearance is reduced by UGT2B15 D85Y polymorphism but unaffected by UGT2B17 deletion. Br J Clin Pharmacol. 2009;68(5):721-30. DOI:10.1111/j.1365-2125.2009.03519.x.

Court M.H., Zhu Z., Masse G., et al. Race, gender, and genetic polymorphism contribute to variability in acetaminophen pharmacokinetics, metabolism, and protein-adduct concentrations in healthy African-American and European-American volunteers. J Pharmacol Exp Ther. 2017;362(3):431- 40. DOI:10.1124/jpet.117.242107.

Савельева М.И., Урванцева И.А., Игнатова А.К., и др. Фармакогенетические особенности II фазы биотрансформации тамоксифена: систематический обзор. Фармакогенетика и Фармакогеномика. 2017;(1):10-5.

Savelyeva M.I., Urvantseva I.A., Ignatova A.K., et al. Pharmacogenetic features of the phase II biotransformation of tamoxifen: a systematic review. Pharmacogenetics and Pharmacogenomics 2017;(1):10-5 (In Russ.)

Ethell B.T., Anderson G.D., Burchell B. The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases. Biochem Pharmacol. 2003;65(9):1441-9. DOI:10.1016/s0006-2952(03)00076-5.

Stringer F., Ploeger B.A., DeJongh J., et al. Evaluation of the impact of UGT polymorphism on the pharmacokinetics and pharmacodynamics of the novel PPAR agonist sipoglitazar. J Clin Pharmacol. 2013;53(3):256-63. DOI:10.1177/0091270012447121.

The authors declare that there are no conflicts of interest present.