Женский пол как фактор риска развития лекарственно-индуцированных заболеваний

Половая принадлежность пациента является одним из значимых факторов, влияющих на риск развития нежелательных реакций при применении лекарственных препаратов. По данным научной литературы, риск развития лекарственно-индуцированных симптомов, синдромов и заболеваний у женщин в 1,5–1,7 раза выше, чем у мужчин. Цель работы: анализ и систематизация данных о причинах, обуславливающих повышенный риск развития лекарственно-индуцированных заболеваний у лиц женского пола. Показано, что более высокий риск развития осложнений фармакотерапии при применении некоторых групп лекарственных препаратов у женщин обусловлен совокупностью факторов, оказывающих влияние на фармакокинетику и фармакодинамику, таких как анатомофизиологические особенности организма, особенности активности/экспрессии ферментов и транспортных белков. Более высокое процентное содержание жировой ткани и более низкое содержание воды в женском организме по сравнению с мужским влияет на объем распределения липофильных препаратов, например опиоидов и бензодиазепинов, вызывая их накопление в организме. У женщин более низкая, чем у мужчин, скорость экскреции и элиминации лекарственных средств почками, что может способствовать развитию нежелательных реакций при применении препаратов, которые выводятся из организма преимущественно с мочой. Изменения гормонального фона при приеме женщинами препаратов половых стероидов с целью заместительной терапии или контрацепции, а также колебания уровня эндогенных половых стероидных гормонов во время менструального цикла, беременности и в перименопаузе за счет связанных с ними изменений объема распределения препарата, активности ферментов цитохрома Р450 и скорости клубочковой фильтрации также могут оказывать влияние на фармакокинетику и фармакодинамику других лекарственных препаратов, что, в свою очередь, отражается на безопасности фармакотерапии. Для повышения безопасности фармакотерапии у лиц женского пола при выборе схемы лечения, в том числе режима дозирования и пути введения лекарственного препарата, необходимо учитывать выявленные особенности фармакокинетики и фармакодинамики лекарственных препаратов у данной категории пациентов.

1. Zhang N, Sundquist J, Sundquist K, Ji J. An increasing trend in the prevalence of polypharmacy in Sweden: a nationwide register-based study. Front Pharmacol. 2020;11:326. https://doi.org/10.3389/fphar.2020.00326

2. Tisdale JE, Miller DA. Drug Induced Diseases: Prevention, Detection, and Management. 3rd ed. Bethesda, Md.: American Society of Health-System Pharmacists; 2018.

3. de Vries ST, Denig P, Ekhart C, Burgers JS, Kleefstra N, Mol PGM, van Puijenbroek EP. Sex differences in adverse drug reactions reported to the National Pharmacovigilance Centre in the Netherlands: an explorative observational study. Br J Clin Pharmacol. 2019;85(7):1507–15. https://doi.org/10.1111/bcp.13923

4. Yu Y, Chen J, Li D, Wang L, Wang W, Liu H. Systematic analysis of adverse event reports for sex differences in adverse drug events. Sci Rep. 2016;6:24955. https://doi.org/10.1038/srep24955

5. Yeon HR, Kang SO, Min KH, Choi Y, Hwang B, Kim HJ, Lee KE. Sex differences in adverse drug reactions using the Korea institute of drug safety and risk management database. Yakhak Hoeji. 2020;64(1 ):79–86 (In Korean). https://doi.org/10.17480/psk.2020.64.1.79

6. Zopf Y, Rabe C, Neubert A, Janson C, Brune K, Hahn EG, Dormann H. Gender-based differences in drug prescription: relation to adverse drug reactions. Pharmacology. 2009;84(6):333–9. https://doi.org/10.1159/000248311

7. Zopf Y, Rabe C, Neubert A, Gassmann KG, Rascher W, Hahn EG, et al. Women encounter ADRs more often than do men. Eur J Clin Pharmacol. 2008;64(10):999–1004. https://doi.org/10.1007/s00228-008-0494-6

8. Joung KI, Jung GW, Park HH, Lee H, Park SH, Shin JY. Gender differences in adverse event reports associated with antidiabetic drugs. Sci Rep. 2020;10:17545. https://doi.org/10.1038/s41598-020-74000-4

9. Kando JC, Yonkers KA, Cole JO. Gender as a risk factor for adverse events to medications. Drugs. 1995;50(1):1–6. https://doi.org/10.2165/00003495-199550010-00001

10. Soldin OP, Chung SH, Mattison DR. Sex differences in drug disposition. J Biomed Biotechnol. 2011;2011:187103. https://doi.org/10.1155/2011/187103

11. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626–38. https://doi.org/10.1038/nri.2016.90

12. Blair ML. Sex-based differences in physiology: what should we teach in the medical curriculum? Adv Physiol Educ. 2007;31(1):23–5. https://doi.org/10.1152/advan.00118.2006

13. Karlstadt RG, Hogan DL, Foxx-Orenstein A. Normal physiology of the gastrointestinal tract and gender differences. In: Legato MJ, ed. Principles of Gender-Specific Medicine. San Diego: Elsevier Academic Press; 2004. P. 377–96. https://doi.org/10.1016/b978-012440905-7/50304-2

14. Yanguas-Casás N. Physiological sex differences in microglia and their relevance in neurological disorders. Neuroimmunol Neuroinflammation. 2020;7:13–22. https://doi.org/10.20517/2347-8659.2019.31

15. Layton AT, Sullivan JC. Recent advances in sex differences in kidney function. Am J Physiol Renal Physiol. 2019;316(2):F328– F331. https://doi.org/10.1152/ajprenal.00584.2018

16. Mennecozzi M, Landesmann B, Palosaari T, Harris G, Whelan M. Sex differences in liver toxicity—do female and male human primary hepatocytes react differently to toxicants in vitro? PLoS ONE. 2015;10(4):e0122786. https://doi.org/10.1371/journal.pone.0122786

17. Soldin OP, Chung SH, Mattison DR. Sex differences in drug disposition. J Biomed Biotechnol. 2011;2011:187103. https://doi.org/10.1155/2011/187103

18. Pampori NA, Shapiro BH. Gender differences in the responsiveness of the sex-dependent isoforms of hepatic P450 to the feminine plasma growth hormone profile. Endocrinology. 1999;140(3):1245–54. https://doi.org/10.1210/endo.140.3.6545

19. Kwo PY, Ramchandani VA, O’Connor S, Amann D, Carr LG, Sandrasegaran K, et al. Gender differences in alcohol metabolism: relationship to liver volume and effect of adjusting for body mass. Gastroenterology. 1998;115(6):1552–7. https://doi.org/10.1016/s0016-5085(98)70035-6

20. Chu T. Gender differences in pharmacokinetics. US Pharm. 2014;39(9):40–3. https://www.uspharmacist.com/article/gender-differences-in-pharmacokinetics

21. Tannenbaum C, Day D, Matera Alliance. Age and sex in drug development and testing for adults. Pharmacol Res. 2017;121:83–93. https://doi.org/10.1016/j.phrs.2017.04.027

22. Moyer AM, Matey ET, Miller VM. Individualized medicine: sex, hormones, genetics, and adverse drug reactions. Pharmacol Res Perspect. 2019;7(6):e00541. https://doi.org/10.1002/prp2.541

23. Waxman DJ, Holloway MG. Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol. 2009;76(2):215–28. https://doi.org/10.1124/mol.109.056705

24. Kobayashi K, Abe C, Endo M, Kazuki Y, Oshimura M, Chiba K. Gender difference of hepatic and intestinal CYP3A4 in CYP3A-humanized mice generated by a human chromosome-engineering technique. Drug Metab Lett. 2017;11(1):60–7. https://doi.org/10.2174/1872312811666170404153804

25. Rasmussen MK, Zamaratskaia G, Ekstrand B. Gender-related differences in cytochrome P450 in porcine liver—implication for activity, expression and inhibition by testicular steroids. Reprod Domest Anim. 2011;46(4):616–23. https://doi.org/10.1111/j.1439-0531.2010.1714.x

26. Franconi F, Campesi I. Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women. Br J Pharmacol. 2014;171(3):580–94. https://doi.org/10.1111/bph.12362

27. van Assema DM, Lubberink M, Rizzu P, van Swieten JC, Schuit RC, Eriksson J, et al. Blood-brain barrier P-glycoprotein function in healthy subjects and Alzheimer’s disease patients: effect of polymorphisms in the ABCB1 gene. EJNMMI Res. 2012;2(1):57. https://doi.org/10.1186/2191-219X-2-57

28. Davison JM, Dunlop W. Renal hemodynamics and tubular function normal human pregnancy. Kidney Int. 1980;18(2):152–61. https://doi.org/10.1038/ki.1980.124

29. Whitley H, Lindsey W. Sex-based differences in drug activity. Am Fam Physician. 2009;80(11):1254–8.

30. Baca E, Garcia-Garcia M, Porras-Chavarino A. Gender differences in treatment response to sertraline versus imipramine in patients with nonmelancholic depressive disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(1):57–65. https://doi.org/10.1016/S0278-5846(03)00177-5

31. Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, et al. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry. 2000;157(9):1445–52. https://doi.org/10.1176/appi.ajp.157.9.1445

32. Bano S, Akhter S, Afridi MI. Gender based response to fluoxetine hydrochloride medication in endogenous depression. J Coll Physicians Surg Pak. 2004;14(3):161–5.

33. Seeman MV. Gender differences in the prescribing of antipsychotic drugs. Am J Psychiatry. 2004;161(8):1324–33. https://doi.org/10.1176/appi.ajp.161.8.1324

34. Melkersson KI, Hulting AL, Rane AJ. Dose requirement and prolactin elevation of antipsychotics in male and female patients with schizophrenia or related psychoses. Br J Clin Pharmacol. 2001;51(4):317–24. https://doi.org/10.1046/j.1365-2125.2001.01352.x

35. Berkley KJ. Sex differences in pain. Behav Brain Sci. 1997;20(3):371–80; discussion 435–513. https://doi.org/10.1017/s0140525x97221485

36. Pleym H, Spigset O, Kharasch ED, Dale O. Gender differences in drug effects: implications for anesthesiologists. Acta Anaesthesiol Scand. 2003;47(3):241–59. https://doi.org/10.1034/j.1399-6576.2003.00036.x

37. Craft RM. Sex differences in drug- and non-drug-induced analgesia. Life Sci. 2003;72(24):2675–88. https://doi.org/10.1016/s0024-3205(03)00178-4

38. Luzier AB, Killian A, Wilton JH, Wilson MF, Forrest A, Kazierad DJ. Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther. 1999;66(6):594–601. https://doi.org/10.1053/cp.1999.v66.103400001

39. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA. 2006;295(3):306–13. https://doi.org/10.1001/jama.295.3.306

40. Cavallari LH, Helgason CM, Brace LD, Viana MA, Nutescu EA. Sex difference in the antiplatelet effect of aspirin in patients with stroke. Ann Pharmacother. 2006;40(5):812–7. https://doi.org/10.1345/aph.1G569

41. Beierle I, Meibohm B, Derendorf H. Gender differences in pharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther. 1999;37(11):529–47. PMID: 10584975

42. Eugene AR, Masiak J. A pharmacodynamic modelling and simulation study identifying gender differences of daily olanzapine dose and dopamine D2-receptor occupancy. Nord J Psychiatry. 2017;71(6):417–24. https://doi.org/10.1080/08039488.2017.1314011

43. Hubacek JA, Dlouha D, Adámkova V, Lanska V, Ceska R, Vrablik M. Possible gene-gender interaction between the SLCO1B1 polymorphism and statin treatment efficacy. Neuro Endocrinol Lett. 2012;33 Suppl 2:22–5. PMID: 23183505

44. Zhou Q, Chen QX, Ruan ZR, Yuan H, Xu HM, Zeng S. CYP2C9*3(1075A>C), ABCB1 and SLCO1B1 genetic polymorphisms and gender are determinants of inter-subject variability in pitavastatin pharmacokinetics. Pharmazie. 2013;68(3):187–94. PMID: 23556337

45. Schuetz EG, Furuya KN, Schuetz JD. Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther. 1995;275(2):1011–8. PMID: 7473127

46. Sabers A. Pharmacokinetic interactions between contraceptives and antiepileptic drugs. Seizure. 2008;17(2):141–4. https://doi.org/10.1016/j.seizure.2007.11.012