russjcardiolРоссийский кардиологический журналRussian Journal of Cardiology1560-40712618-7620«SILICEA-POLIGRAF» LLC10.15829/1560-4071-2024-5829GJICGYrussjcardiol-5829Research ArticleКЛИНИКА И ФАРМАКОТЕРАПИЯ. МНЕНИЕ ПО ПРОБЛЕМЕВклад липофильности в клинические эффекты лекарственного препаратаContribution of lipophilicity to the clinical effects of drugshttps://orcid.org/0000-0002-8856-3638СкотниковА. С.SkotnikovA. S.

Доцент кафедры медико-социальной экспертизы, неотложной и поликлинической терапии Института профессионального образования; зав. кафедрой фармакологии и клинической фармакологии Высшей медицинской школы; руководитель.

Москва

Moscow

skotnikov.as@mail.ruhttps://orcid.org/0000-0001-8800-4628МельникМ. В.MelnikM. V.

Профессор кафедры медико-социальной экспертизы, неотложной и поликлинической терапии Института профессионального образования.

Москва

Moscow

https://orcid.org/0009-0001-2120-8172ЗининаЕ. А.ZininaE. A.

Ассистент кафедры фармакологии и клинической фармакологии Высшей медицинской школы.

Москва

Moscow

https://orcid.org/0000-0002-8685-188XСиверцеваИ. В.SivertsevaI. V.

м. н. с., ORCID: 0000-0002-8685-188X.

Москва

Moscow

ФГАОУ ВО Первый МГМУ им. И.М. Сеченова Минздрава России (Сеченовский Университет); ФГБУО ВО Российский государственный социальный университет; АНО Научно-исследовательский центр коморбидной патологии "Рациональная медицина"РоссияI.M. Sechenov First Moscow State Medical University; Russian State Social University; Research Center for Comorbid Pathology "Rational Medicine"Russian FederationФГАОУ ВО Первый МГМУ им. И.М. Сеченова Минздрава России (Сеченовский Университет)РоссияI.M. Sechenov First Moscow State Medical UniversityRussian FederationФГБУО ВО Российский государственный социальный университетРоссияRussian State Social UniversityRussian FederationАНО Научно-исследовательский центр коморбидной патологии "Рациональная медицина"РоссияRussian State Social University; Research Center for Comorbid Pathology "Rational Medicine"Russian Federation20241704202429358295829Copyright © Скотников А.С., Мельник М.В., Зинина Е.А., Сиверцева И.В., 20242024Скотников А.С., Мельник М.В., Зинина Е.А., Сиверцева И.В.Skotnikov A.S., Melnik M.V., Zinina E.A., Sivertseva I.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://russjcardiol.elpub.ru/jour/article/view/5829

Статья посвящена подробному разбору особенностей действия различных лекарственных средств, применяемых в терапии артериальной гипертензии и атерогенной дислипидемии в зависимости от их способности к растворению в жировых средах организма (липофильность). Авторы проводят связь между выраженностью степени липофильности лекарственных веществ и парамет­рами их фармакокинетики, нюансами межлекарственных взаимодействий, проявлениями клинических эффектов и органопротекции, а также их способностью влиять на прогноз коморбидных больных. На примере ингибиторов ангиотензинпревращающего фермента, блокаторов кальциевых каналов и статинов авторы разъясняют прикладное значение таких фармакологических показателей, как связывание с белками плазмы крови и объём распределения, а также формируют у читателя понимание значимости рутинного использования этих величин с целью получения клинических выгод для своих пациентов.

The article is devoted to a detailed analysis of the action of various drugs used in the treatment of hypertension and atherogenic dyslipidemia, depending on their ability to dissolve in fatty media (lipophilicity). The authors analyze connection between the lipophilicity level of drugs and their pharmacokinetics, drug-drug interactions, the manifestations of clinical effects and organ protection, as well as their ability to influence the prognosis of comorbid patients. Using angiotensin-converting enzyme inhibitors, calcium channel blockers, and statins as examples, the authors explain the practical significance of pharmacological parameters such as plasma protein binding and distribution volume, and also develop an un­derstanding of the importance of its routine use in order to obtain clinical bene­fits for patients.

липофильностьорганопротекциякоморбидностьартериальная гипертензияатерогенная дислипидемияlipophilicityorgan protectioncomorbidityhypertensionatherogenic dyslipidemiaСтатья подготовлена при поддержке компании СервьеThis article was supported by the Servier CompanyReferencesWaring MJ. Lipophilicity in drug discovery. Expert Opin Drug Discov. 2010;5(3):235-48. doi:10.1517/17460441003605098.Waring MJ. Lipophilicity in drug discovery. Expert Opin Drug Discov. 2010;5(3):235-48. doi:10.1517/17460441003605098.Lewis DF, Dickins M. Baseline lipophilicity relationships in human cytochromes P450 associated with drug metabolism. Drug Metab Rev. 2003;35(1):1-18. doi:10.1081/dmr-120018245.Lewis DF, Dickins M. Baseline lipophilicity relationships in human cytochromes P450 associated with drug metabolism. Drug Metab Rev. 2003;35(1):1-18. doi:10.1081/dmr-120018245.Arnott JA, Planey SL. The influence of lipophilicity in drug discovery and design. Expert Opin Drug Discov. 2012;7(10):863-75. doi:10.1517/17460441.2012.714363.Arnott JA, Planey SL. The influence of lipophilicity in drug discovery and design. Expert Opin Drug Discov. 2012;7(10):863-75. doi:10.1517/17460441.2012.714363.Testa B, Crivori, P, Reist M, et al. The influence of lipophilicity on the pharmacokinetic behavior of drugs: Concepts and examples. Perspectives in Drug Discovery and Design. 2000;19:179-211. doi:10.1023/A:1008741731244.Testa B, Crivori, P, Reist M, et al. The influence of lipophilicity on the pharmacokinetic behavior of drugs: Concepts and examples. Perspectives in Drug Discovery and Design. 2000;19:179-211. doi:10.1023/A:1008741731244.Zaro JL. Lipid-based drug carriers for prodrugs to enhance drug delivery. AAPS J. 2015;17(1):83-92. doi:10.1208/s12248-014-9670-z.Zaro JL. Lipid-based drug carriers for prodrugs to enhance drug delivery. AAPS J. 2015;17(1):83-92. doi:10.1208/s12248-014-9670-z.Brugts JJ, Ferrari R, Simoons ML. Angiotensin-converting enzyme inhibition by perindo­pril in the treatment of cardiovascular disease. Expert Rev Cardiovasc Ther. 2009;7(4): 345-60. doi:10.1586/erc.09.2.Brugts JJ, Ferrari R, Simoons ML. Angiotensin-converting enzyme inhibition by perindo­pril in the treatment of cardiovascular disease. Expert Rev Cardiovasc Ther. 2009;7(4): 345-60. doi:10.1586/erc.09.2.Irby D, Du C, Li F. Lipid-Drug Conjugate for Enhancing Drug Delivery. Mol Pharm. 2017;14(5):1325-38. doi:10.1021/acs.molpharmaceut.6b01027.Irby D, Du C, Li F. Lipid-Drug Conjugate for Enhancing Drug Delivery. Mol Pharm. 2017;14(5):1325-38. doi:10.1021/acs.molpharmaceut.6b01027.Jacob M, Chappell D, Rehm M. "The 'third space'—fact or fiction?" Best Pract Res Clin Anaesthesiol. 2009;23(2):145-57. doi:10.1016/j.bpa.2009.05.001.Jacob M, Chappell D, Rehm M. "The 'third space'—fact or fiction?" Best Pract Res Clin Anaesthesiol. 2009;23(2):145-57. doi:10.1016/j.bpa.2009.05.001.Rhoades RA, Bell DR. Medical Physiology: Principles for Clinical Medicine. Lippincott Williams & Wilkins. 2012, pp. 5-6. ISBN: 978-1-60913-427-3.Rhoades RA, Bell DR. Medical Physiology: Principles for Clinical Medicine. Lippincott Williams & Wilkins. 2012, pp. 5-6. ISBN: 978-1-60913-427-3.Tsopelas F, Giaginis C, Tsantili-Kakoulidou A. Lipophilicity and biomimetic properties to support drug discovery. Expert Opin Drug Discov. 2017;12(9):885-96. doi:10.1080/17460441.2017.1344210.Tsopelas F, Giaginis C, Tsantili-Kakoulidou A. Lipophilicity and biomimetic properties to support drug discovery. Expert Opin Drug Discov. 2017;12(9):885-96. doi:10.1080/17460441.2017.1344210.Zhu Q, Li X, Xia D, et al. Lipid-Based Formulations for Oral Drug Delivery: Effects on Drug Absorption and Metabolism. Curr Drug Metab. 2015;16(3):200-10. doi:10.2174/138920021603150812121453.Zhu Q, Li X, Xia D, et al. Lipid-Based Formulations for Oral Drug Delivery: Effects on Drug Absorption and Metabolism. Curr Drug Metab. 2015;16(3):200-10. doi:10.2174/138920021603150812121453.Ginex T, Vazquez J, Gilbert E, et al. Lipophilicity in drug design: an overview of lipophilicity descriptors in 3D-QSAR studies. Future Med Chem. 2019;11(10):1177-93. doi:10.4155/fmc-2018-0435.Ginex T, Vazquez J, Gilbert E, et al. Lipophilicity in drug design: an overview of lipophilicity descriptors in 3D-QSAR studies. Future Med Chem. 2019;11(10):1177-93. doi:10.4155/fmc-2018-0435.Xiong G, Wu Z, Yi J, et al. ADMETlab 2.0: an integrated online platform for accura­te and comprehensive predictions of ADMET properties. Nucleic Acids Res. 2021;49(W1):W5-W14. doi:10.1093/nar/gkab255.Xiong G, Wu Z, Yi J, et al. ADMETlab 2.0: an integrated online platform for accura­te and comprehensive predictions of ADMET properties. Nucleic Acids Res. 2021;49(W1):W5-W14. doi:10.1093/nar/gkab255.Bruno CD, Harmatz JS, Duan SX, et al. Effect of lipophilicity on drug distribution and elimination: Influence of obesity. Br J Clin Pharmacol. 2021;87(8):3197-205. doi:10.1111/bcp.14735.Bruno CD, Harmatz JS, Duan SX, et al. Effect of lipophilicity on drug distribution and elimination: Influence of obesity. Br J Clin Pharmacol. 2021;87(8):3197-205. doi:10.1111/bcp.14735.Ruschitzka FT, Lüscher TF. Is there a rationale for combining angiotensin-converting enzyme inhibitors and calcium antagonists in cardiovascular disease? Am Heart J. 1997;134(2 Pt 2):S31-47. doi:10.1016/s0002-8703(97)70007-3.Ruschitzka FT, Lüscher TF. Is there a rationale for combining angiotensin-converting enzyme inhibitors and calcium antagonists in cardiovascular disease? Am Heart J. 1997;134(2 Pt 2):S31-47. doi:10.1016/s0002-8703(97)70007-3.Phillips JE, Preston Mason R. Inhibition of oxidized LDL aggregation with the calcium channel blocker amlodipine: role of electrostatic interactions. Atherosclerosis. 2003;168(2):239-44. doi:10.1016/s0021-9150(03)00102-3.Phillips JE, Preston Mason R. Inhibition of oxidized LDL aggregation with the calcium channel blocker amlodipine: role of electrostatic interactions. Atherosclerosis. 2003;168(2):239-44. doi:10.1016/s0021-9150(03)00102-3.Mason RP, Walter MF, Trumbore MW, et al. Membrane antioxidant effects of the charged dihydropyridine calcium antagonist amlodipine. J Mol Cell Cardiol. 1999;31(1):275-81. doi:10.1006/jmcc.1998.0867.Mason RP, Walter MF, Trumbore MW, et al. Membrane antioxidant effects of the charged dihydropyridine calcium antagonist amlodipine. J Mol Cell Cardiol. 1999;31(1):275-81. doi:10.1006/jmcc.1998.0867.Mason RP, Campbell SF, Wang SD, Herbette LG. Comparison of location and binding for the positively charged 1,4-dihydropyridine calcium channel antagonist amlodipine with uncharged drugs of this class in cardiac membranes. Mol Pharmacol. 1989;36(4):634-40.Mason RP, Campbell SF, Wang SD, Herbette LG. Comparison of location and binding for the positively charged 1,4-dihydropyridine calcium channel antagonist amlodipine with uncharged drugs of this class in cardiac membranes. Mol Pharmacol. 1989;36(4):634-40.Murdoch D, Heel RC. Amlodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease. Drugs. 1991;41(3):478-505. doi:10.2165/00003495-199141030-00009.Murdoch D, Heel RC. Amlodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease. Drugs. 1991;41(3):478-505. doi:10.2165/00003495-199141030-00009.Кукес В. Г., Сычев Д. А., Ших Е. В. и др. "Клиническая фармакология" (учебник под ред. В. Г. Кукеса, 6-е издание, исправленное и дополненное), Москва: Гэотар-Медиа, 2022, с. 1024, ISBN: 597046807X.Kukes VG, Sychev DA, Shikh EV, et al. "Clinical pharmacology", Moscow: Geotar-Media, 2022, p. 1024. (In Russ.) ISBN: 597046807X.Bytyçi I, Bajraktari G, Bhatt DL, et al. Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Hydrophilic vs lipophilic statins in coronary artery disease: A meta-analysis of randomized controlled trials. J Clin Lipidol. 2017;11(3):624-37. doi:10.1016/j.jacl.2017.03.003.Bytyçi I, Bajraktari G, Bhatt DL, et al. Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Hydrophilic vs lipophilic statins in coronary artery disease: A meta-analysis of randomized controlled trials. J Clin Lipidol. 2017;11(3):624-37. doi:10.1016/j.jacl.2017.03.003.Liu G, Zheng XX, Xu YL, et al. Effects of lipophilic statins for heart failure: a meta-analysis of 13 randomised controlled trials. Heart Lung Circ. 2014;23(10):970-7. doi:10.1016/j.hlc.2014.05.005.Liu G, Zheng XX, Xu YL, et al. Effects of lipophilic statins for heart failure: a meta-analysis of 13 randomised controlled trials. Heart Lung Circ. 2014;23(10):970-7. doi:10.1016/j.hlc.2014.05.005.Banach M, Rizzo M, Toth PP, et al. Statin intolerance — an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci. 2015;11:1-23. doi:10.5114/aoms.2015.49807.Banach M, Rizzo M, Toth PP, et al. Statin intolerance — an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci. 2015;11:1-23. doi:10.5114/aoms.2015.49807.Jamal SM, Eisenberg MJ, Christopoulos S. Rhabdomyolysis associated with hydro­xymethylglutaryl-coenzyme A reductase inhibitors. Am Heart J. 2004;147:956-65. doi:10.1016/j.ahj.2003.12.037.Jamal SM, Eisenberg MJ, Christopoulos S. Rhabdomyolysis associated with hydro­xymethylglutaryl-coenzyme A reductase inhibitors. Am Heart J. 2004;147:956-65. doi:10.1016/j.ahj.2003.12.037.Roberts WC. The underused miracle drugs: the statin drugs are to atherosclerosis what penicillin was to infectious disease. Am J Cardiol. 1996;78:377-8. doi:10.1016/s0002-9149(96)00441-9.Roberts WC. The underused miracle drugs: the statin drugs are to atherosclerosis what penicillin was to infectious disease. Am J Cardiol. 1996;78:377-8. doi:10.1016/s0002-9149(96)00441-9.Veillard NR, Mach F. Statins: the new aspirin? Cell Mol Life Sci. 2002;59:1771-86. doi:10.1007/pl00012505.Veillard NR, Mach F. Statins: the new aspirin? Cell Mol Life Sci. 2002;59:1771-86. doi:10.1007/pl00012505.Wiseman LR, McTavish D. Trandolapril. A review of its pharmacodynamic and pharma­cokinetic properties, and therapeutic use in essential hypertension. Drugs. 1994;48(1): 71-90. doi:10.2165/00003495-199448010-00007.Wiseman LR, McTavish D. Trandolapril. A review of its pharmacodynamic and pharma­cokinetic properties, and therapeutic use in essential hypertension. Drugs. 1994;48(1): 71-90. doi:10.2165/00003495-199448010-00007.Raevsky OA, Fetisov VI, Trepalina EP, et al. Quantitative estimation of drug absorption in humans for passively transported compounds on the basis of their physico-chemical parameters. Quant. Struct.-Act. Relat. 2000;19:366-74.Raevsky OA, Fetisov VI, Trepalina EP, et al. Quantitative estimation of drug absorption in humans for passively transported compounds on the basis of their physico-chemical parameters. Quant. Struct.-Act. Relat. 2000;19:366-74.Сидоренко Б. А., Преображенский Д. В. В кн.: Ингибиторы ангиотензинпревращающего фермента. М, Литтерра, 2007; 351 с. ISBN: 978-5-98216-097-3.Sidorenko BA, Preobrazhensky DV. In the book: Angiotensin-converting enzyme inhibitors. Litterra, 2007; 351 р. (In Russ.) ISBN: 978-5-98216-097-3.Wang XZ, Yu ZX, Nie B, Chen DM. Perindopril inhibits myocardial apoptosis in mice with acute myocardial infarction through TLR4/NF-κB pathway. Eur Rev Med Pharmacol Sci. 2019;23(15):6672-82. doi:10.26355/eurrev_201908_18558.Wang XZ, Yu ZX, Nie B, Chen DM. Perindopril inhibits myocardial apoptosis in mice with acute myocardial infarction through TLR4/NF-κB pathway. Eur Rev Med Pharmacol Sci. 2019;23(15):6672-82. doi:10.26355/eurrev_201908_18558.Baer JT, Sauer WH, Berlin JA, Kimmel SE. Comparison of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the primary prevention of myocardial infarction in hypertensive patients. Am J Cardiol. 2004;94(4):479-81. doi:10.1016/j.amjcard.2004.04.063.Baer JT, Sauer WH, Berlin JA, Kimmel SE. Comparison of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the primary prevention of myocardial infarction in hypertensive patients. Am J Cardiol. 2004;94(4):479-81. doi:10.1016/j.amjcard.2004.04.063.Pilote L, Abrahamowicz M, Rodrigues E, et al. Mortality rates in elderly patients who take different angiotensin-converting enzyme inhibitors after acute myocardial infarction: a class effect? Ann Intern Med. 2004;141(2):102-12. doi:10.7326/0003-4819-141-2-200407200-00008.Pilote L, Abrahamowicz M, Rodrigues E, et al. Mortality rates in elderly patients who take different angiotensin-converting enzyme inhibitors after acute myocardial infarction: a class effect? Ann Intern Med. 2004;141(2):102-12. doi:10.7326/0003-4819-141-2-200407200-00008.Tschudi MR, Noll G, Lüscher TP. Pharmakotherapie der Arteriosklerose und ihrer Komplikationen. Wirkung von ACE-Inhibitoren und HMG-CoA-Reduktase-Hemmern [Pharmacotherapy of arteriosclerosis and its complications. Effect of ACE inhibitors and HMG-CoA-reductase inhibitors]. Schweiz Med Wochenschr. 1997;127(15):636-49. German.Tschudi MR, Noll G, Lüscher TP. Pharmakotherapie der Arteriosklerose und ihrer Komplikationen. Wirkung von ACE-Inhibitoren und HMG-CoA-Reduktase-Hemmern [Pharmacotherapy of arteriosclerosis and its complications. Effect of ACE inhibitors and HMG-CoA-reductase inhibitors]. Schweiz Med Wochenschr. 1997;127(15):636-49. German.Cicero AFG, Fogacci F, Rizzoli E, et al.; Brisighella Heart Study Group. Impact of simu­ltaneous management of hypertension and hypercholesterolemia with ACE inhibitors and statins on cardiovascular outcomes in the Brisighella Heart Study: A 8-year follow-up. Nutr Metab Cardiovasc Dis. 2022;32(9):2246-54. doi:10.1016/j.numecd.2022.06.017.Cicero AFG, Fogacci F, Rizzoli E, et al.; Brisighella Heart Study Group. Impact of simu­ltaneous management of hypertension and hypercholesterolemia with ACE inhibitors and statins on cardiovascular outcomes in the Brisighella Heart Study: A 8-year follow-up. Nutr Metab Cardiovasc Dis. 2022;32(9):2246-54. doi:10.1016/j.numecd.2022.06.017.

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