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Buprenorfin Farmakokinetiğinde ve Farmakodinamiğinde Rol Oynayan Gen Polimorfizmleri: Genel Bakış

Yıl 2023, Cilt: 24 Sayı: 3, 391 - 401, 30.09.2023
https://doi.org/10.51982/bagimli.1203151

Öz

Buprenorfin opioid bağımlılığının tedavisinde etkili olmasına rağmen, opioid kullanıcıları arasında nüksetme ve/veya tedaviyi bırakmak gibi nedenlerle tedavi başarısızlığı oranı yüksektir. Bu da sağlık hizmetleri ve adalet açısından topluma önemli maliyetlere yol açmaktadır. Opioid kullanım bozukluğu için farmakoterapilerin etkinliğinin %60-70 arasında olduğu tahmin edilmektedir. Tedavi etkinliğini artırmak ve yüksek olan tedaviyi bırakma oranlarını azaltmak için, hastaların genetik profil gibi bireysel özelliklerinin daha detaylı anlaşılması önem arz etmektedir. Tedaviye yanıt verme ile ilaçların metabolizmasını, etki mekanizmasını ve taşınmasını düzenleyen genetik varyantlar arasında bir etkileşim olduğu yaygın olarak kabul edilmektedir. Bu nedenle, hastaya göre tedavi uygulaması, tedavi sonuçlarının iyileştirmesi ve ayrıca tedavi başarısızlığı riski yüksek olan bağımlılarda daha uzun süren yoksunluk dönemlerininin kolaylaştırılması için iyi bir yaklaşım olacaktır. Opioid kullanım bozukluğu tedavisinde buprenorfin dozunun bireyselleştirilmesi ve buprenorfin dozu ile etkinlik arasındaki ilişkiyi anlamak için daha fazla çalışmaya gerek vardır.

Kaynakça

  • 1. Ettienne EB, Chapman E, Maneno M, et al. Pharmacogenomics-guided policy in opioid use disorder (OUD) management: an ethnically-diverse case-based approach. Addict Behav Rep 2017; 6: 8–14.
  • 2. Ettienne EB, Ofoegbu A, Maneno MK, et al. Pharmacogenomics and opioid use disorder: clinical decision support in an African American cohort. J Natl Med Assoc 2019; 111(6): 674-681.
  • 3. Kaya-Akyüzlü D, Özkan-Kotiloğlu S, Bal C, et al. Effects of UGT2B7 rs7662029 and rs7439366 polymorphisms on sublingual buprenorphine metabolism in heroin addicts: an improved PCR-RFLP assay for the detection of rs7662029 polymorphism. Environ Toxicol Pharmacol 2022; 94: 103902.
  • 4. Imai H, Morita M, Morita H, et al. The μ-opioid receptor gene polymorphism 118A>G weakens the pharmacological action of buprenorphine. Int J Clin Pharmacol Ther 2020; 58(11): 626-633.
  • 5. Crist RC, Clarke TK, Ang A, et al. An intronic variant in OPRD1 predicts treatment outcome for opioid dependence in African-Americans. Neuropsychopharmacology 2013; 38(10): 2003-2010.
  • 6. U.S. Food and Drug Administation, 2002. Center for Drug Evaluation and Research. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020733s007s008lbl.pdf. (Accessed 15.12.2021)
  • 7. Davis MP, Pasternak G, Behm B. Treating chronic pain: an overview of clinical studies centered on the buprenorphine option. Drugs 2018; 78(12): 1211–1228.
  • 8. Brown SM, Holtzman M, Kim T, Kharasch ED. Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active. Anesthesiology 2011; 115(6): 1251–1260.
  • 9. Fihlman M, Hemmilä T, Hagelberg NM, et al. Voriconazole greatly increases the exposure to oral buprenorphine. Eur J Clin Pharmacol 2018; 74(12): 1615-1622.
  • 10. Crettol S, Déglon JJ, Besson J, et al. ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther 2006; 80(6): 668-681.
  • 11. Peng S, Jiang H, Du J, et al. Methadone dosage and plasma levels, SNPs of OPRM1 gene and age of first drug use were associated with outcomes of methadone maintenance treatment. Front Genet 2018; 9: 450.
  • 12. Kaya-Akyüzlü D, Özkan-Kotiloğlu S, Bal C, et al. Sublingual buprenorphine/naloxone treatment is not affected by OPRM1 A118G and BDNF Va66Met polymorphisms, but alters the plasma beta-endorphin and BDNF levels in individuals with opioid use disorder. Environ Toxicol Pharmacol 2022; 95: 103979.
  • 13. Muriel J, Margarit C, Planelles B, et al. OPRM1 influence on and effectiveness of an individualized treatment plan for prescription opioid use disorder patients. Ann N Y Acad Sci 2018; 1425(1): 82-93.
  • 14. Kreek MJ, Reed B, Butelman ER. Current status of opioid addiction treatment and related preclinical research. Sci Adv 2019; 5(10): eaax9140.
  • 15. Welsch L, Bailly J, Darcq E, Kieffer BL. The negative affect of protracted opioid abstinence: progress and perspectives from rodent models. Biol Psychiatry 2020; 87(1): 54-63.
  • 16. Pathan H, Williams J. Basic opioid pharmacology: an update. Br J Pain 2012; 6(1): 11-16.
  • 17. Mysels D. The kappa-opiate receptor impacts the pathophysiology and behavior of substance use. Am J Addict 2009; 18(4): 272–276.
  • 18. Karkhanis A, Holleran KM, Jones SR. Dynorphin/kappa opioid receptor signaling in preclinical models of alcohol, drug, and food addiction. Int Rev Neurobiol 2017; 136: 53-88.
  • 19. Lalanne L, Ayranci G, Kieffer BL, Lutz PE. The kappa opioid receptor: from addiction to depression, and back. Front Psychiatry 2014; 5: 170.
  • 20. Borg L, Buonora M, Butelman ER, et al. The Pharmacology of Opioids. Ries RK, Fiellin DA, Miller SC, Saitz R (editors). 5. Baskı, Philadelphia: Wolters Kluwer Health, 2014:135‐50.
  • 21. Avrupa Uyuşturucu Raporu 2019. https://doi.org/doi/10.2810/760305 (28 Haziran 2019’da ulaşıldı.)
  • 22. Kakko J, Alho H, Baldacchino A, et al. Craving in opioid use disorder: from neurobiology to clinical practice. Front Psychiatry 2019; 10: 592.
  • 23. Wang YH, Sun JF, Tao YM, et al. The role of kappa-opioid receptor activation in mediating antinociception and addiction. Acta Pharmacol Sin 2010; 31(9): 1065-1070.
  • 24. Lutz PE, Ayranci G, Chu-Sin-Chung P, et al. Distinct mu, delta, and kappa opioid receptor mechanisms underlie low sociability and depressive-like behaviors during heroin abstinence. Neuropsychopharmacology 2014; 39(11): 2694-2705.
  • 25. Yılmaz A, Can Y, Bozkurt M, Evren C. Alkol ve madde bağımlılığında remisyon ve depreşme. Psikiyatride Güncel Yaklaşımlar 2014; 6(3): 243-256.
  • 26. Kadam M, Sinha A, Nimkar S, et al. A comparative study of factors associated with relapse in alcohol dependence and opioid dependence. Indian J Psychol Med 2017; 39(5): 627-633.
  • 27. Smyth BP, Barry J, Keenan E, Ducray K. Lapse and relapse following inpatient treatment of opiate dependence. Ir Med J 2010; 103(6): 176-179.
  • 28. Xu K, Seo D, Hodgkinson C, et al. A variant on the kappa opioid receptor gene (OPRK1) is associated with stress response and related drug craving, limbic brain activation and cocaine relapse risk. Transl Psychiatry 2013; 3(8): e292.
  • 29. Strang J, Volkow ND, Degenhardt L, et al. Opioid use disorder. Nat Rev Dis Primers 2020; 6(1): 3.
  • 30. Clarke TK, Crist RC, Ang A, et al. Genetic variation in OPRD1 and the response to treatment for opioid dependence with buprenorphine in European American females. Pharmacogenomics J 2014; 14(3): 303–308.
  • 31. Evren C, Karadağ F. Alkol ve Madde Kullanım Bozuklukları Tedavi ve İzlem Klinik Protokolü. Ankara: T.C. Sağlık Bakanlığı, 2022.
  • 32. Cone EJ, Gorodetzky CW, Yousefnejad D, et al. The metabolism and excretion of buprenorphine in humans. Drug Metab Dispos 1984; 12(5): 577-581.
  • 33. Walter DS, Inturrisi CE. Absorption, distribution, metabolism, and excretion of buprenorphine in animals and humans. Cowan A, Lewis JW (editors). Buprenorphine: combatting drug abuse with a unique opioid. New York: Wiley-Liss; 1995. 113–135.
  • 34. Seguí HA, Melin K, Quiñones DS, Duconge J. A review of the pharmacogenomics of buprenorphine for the treatment of opioid use disorder. J Transl Genet Genom 2020; 4: 263–277.
  • 35. Yiannakopoulou, E. Pharmacogenomics and opioid analgesics: clinical implications. Int J Genomics 2015; 2015: 368979.
  • 36. Chawarski MC, Schottenfeld RS, O'Connor PG, Pakes J. Plasma concentrations of buprenorphine 24 to 72 hours after dosing. Drug Alcohol Depend 1999; 55(1-2): 157-163.
  • 37. Laib AK, Böttcher M, Hiemke C, Havemann-Reinecke U. Therapeutic drug-monitoring for opiate-dependent patients receiving buprenorphine for substitution. Pharmacopsychiatry 2013; 46: A32.
  • 38. Weber WW. Populations and genetic polymorphisms. Mol Diagn 1999; 4(4): 299-307.
  • 39. Roy JN, Lajoie J, Zijenah LS, et al. CYP3A5 genetic polymorphisms in different ethnic populations. Drug Metab Dispos. 2005; 33(7): 884-887.
  • 40. Sastre JA, Varela G, López M, et al. Influence of uridine diphosphate-glucuronyltransferase 2b7 (UGT2B7) variants on postoperative buprenorphine analgesia. Pain Pract 2015; 15(1): 22-30.
  • 41. Blanco F, Muriel C, Labrador J, et al. Influence of UGT2B7, CYP3A4, and OPRM1 gene polymorphisms on transdermal buprenorphine pain control in patients with critical lower limb ischemia awaiting revascularization. Pain Pract 2016; 16(7): 842-849.
  • 42. Taqi MM, Faisal M, Zaman H. OPRM1 A118G polymorphisms and its role in opioid addiction: implication on severity and treatment approaches. Pharmgenomics Pers Med 2019; 12: 361-368.
  • 43. Beer B, Erb R, Pavlic M, et al. Association of polymorphisms in pharmacogenetic candidate genes (OPRD1, GAL, ABCB1, OPRM1) with opioid dependence in European population: a case-control study. PLoS One 2013; 8(9): e75359.
  • 44. Crist RC, Doyle GA, Nelson EC, et al. A polymorphism in the OPRM1 3'-untranslated region is associated with methadone efficacy in treating opioid dependence. Pharmacogenomics J 2018; 18(1): 173-179.
  • 45. Crist RC, Phillips KA, Furnari MA, et al. Replication of the pharmacogenetic effect of rs678849 on buprenorphine efficacy in African-Americans with opioid use disorder. Pharmacogenomics J 2019; 19(3): 260-268.
  • 46. Kranzler HR, Lynch KG, Crist RC, et al. A delta-opioid receptor gene polymorphism moderates the therapeutic response to extended-release buprenorphine in opioid use disorder. Int J Neuropsychopharmacol 2021; 24(2): 89-96.
  • 47. Gerra G, Somaini L, Leonardi C, et al. Association between gene variants and response to buprenorphine maintenance treatment. Psychiatry Res 2014; 215(1): 202-207.
  • 48. Picard N, Cresteil T, Djebli N, Marquet P. In vitro metabolism study of buprenorphine: evidence for new metabolic pathways. Drug Metab Dispos 2005; 33: 689-695.
  • 49. Liao MZ, Gao C, Shireman LM, et al. P-gp/ABCB1 exerts differential impacts on brain and fetal exposure to norbuprenorphine. Pharmacol Res 2017; 119: 61-71.

Gene Polymorphisms Playing Roles in Pharmacokinetics and Pharmacodynamics of Buprenorphine: An Overview

Yıl 2023, Cilt: 24 Sayı: 3, 391 - 401, 30.09.2023
https://doi.org/10.51982/bagimli.1203151

Öz

Although buprenorphine is effective in the treatment of opioid use disorder, treatment failure rates are high among opioid users due to relapse and/or drop-out. This leads to significant costs to society in terms of health services and justice. The efficacy of pharmacotherapy for opioid use disorder is estimated to be between 60-70%. It is important to understand the individual characteristics of patients, such as genetic profile in detail to increase the effectiveness of treatment and reduce the high drop-out rates. It is widely accepted that there is an interaction between responsiveness to treatment and genetic variants that regulate the metabolism, mechanism of action and transport of drugs. Therefore, individualized treatment would be a good approach to improve treatment outcomes and also to facilitate longer periods of abstinence in opioid users at high risk of treatment failure. More studies are needed to understand the individualization of buprenorphine dose and the relationship between buprenorphine dose and efficacy in the treatment of opioid use disorder.

Kaynakça

  • 1. Ettienne EB, Chapman E, Maneno M, et al. Pharmacogenomics-guided policy in opioid use disorder (OUD) management: an ethnically-diverse case-based approach. Addict Behav Rep 2017; 6: 8–14.
  • 2. Ettienne EB, Ofoegbu A, Maneno MK, et al. Pharmacogenomics and opioid use disorder: clinical decision support in an African American cohort. J Natl Med Assoc 2019; 111(6): 674-681.
  • 3. Kaya-Akyüzlü D, Özkan-Kotiloğlu S, Bal C, et al. Effects of UGT2B7 rs7662029 and rs7439366 polymorphisms on sublingual buprenorphine metabolism in heroin addicts: an improved PCR-RFLP assay for the detection of rs7662029 polymorphism. Environ Toxicol Pharmacol 2022; 94: 103902.
  • 4. Imai H, Morita M, Morita H, et al. The μ-opioid receptor gene polymorphism 118A>G weakens the pharmacological action of buprenorphine. Int J Clin Pharmacol Ther 2020; 58(11): 626-633.
  • 5. Crist RC, Clarke TK, Ang A, et al. An intronic variant in OPRD1 predicts treatment outcome for opioid dependence in African-Americans. Neuropsychopharmacology 2013; 38(10): 2003-2010.
  • 6. U.S. Food and Drug Administation, 2002. Center for Drug Evaluation and Research. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020733s007s008lbl.pdf. (Accessed 15.12.2021)
  • 7. Davis MP, Pasternak G, Behm B. Treating chronic pain: an overview of clinical studies centered on the buprenorphine option. Drugs 2018; 78(12): 1211–1228.
  • 8. Brown SM, Holtzman M, Kim T, Kharasch ED. Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active. Anesthesiology 2011; 115(6): 1251–1260.
  • 9. Fihlman M, Hemmilä T, Hagelberg NM, et al. Voriconazole greatly increases the exposure to oral buprenorphine. Eur J Clin Pharmacol 2018; 74(12): 1615-1622.
  • 10. Crettol S, Déglon JJ, Besson J, et al. ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther 2006; 80(6): 668-681.
  • 11. Peng S, Jiang H, Du J, et al. Methadone dosage and plasma levels, SNPs of OPRM1 gene and age of first drug use were associated with outcomes of methadone maintenance treatment. Front Genet 2018; 9: 450.
  • 12. Kaya-Akyüzlü D, Özkan-Kotiloğlu S, Bal C, et al. Sublingual buprenorphine/naloxone treatment is not affected by OPRM1 A118G and BDNF Va66Met polymorphisms, but alters the plasma beta-endorphin and BDNF levels in individuals with opioid use disorder. Environ Toxicol Pharmacol 2022; 95: 103979.
  • 13. Muriel J, Margarit C, Planelles B, et al. OPRM1 influence on and effectiveness of an individualized treatment plan for prescription opioid use disorder patients. Ann N Y Acad Sci 2018; 1425(1): 82-93.
  • 14. Kreek MJ, Reed B, Butelman ER. Current status of opioid addiction treatment and related preclinical research. Sci Adv 2019; 5(10): eaax9140.
  • 15. Welsch L, Bailly J, Darcq E, Kieffer BL. The negative affect of protracted opioid abstinence: progress and perspectives from rodent models. Biol Psychiatry 2020; 87(1): 54-63.
  • 16. Pathan H, Williams J. Basic opioid pharmacology: an update. Br J Pain 2012; 6(1): 11-16.
  • 17. Mysels D. The kappa-opiate receptor impacts the pathophysiology and behavior of substance use. Am J Addict 2009; 18(4): 272–276.
  • 18. Karkhanis A, Holleran KM, Jones SR. Dynorphin/kappa opioid receptor signaling in preclinical models of alcohol, drug, and food addiction. Int Rev Neurobiol 2017; 136: 53-88.
  • 19. Lalanne L, Ayranci G, Kieffer BL, Lutz PE. The kappa opioid receptor: from addiction to depression, and back. Front Psychiatry 2014; 5: 170.
  • 20. Borg L, Buonora M, Butelman ER, et al. The Pharmacology of Opioids. Ries RK, Fiellin DA, Miller SC, Saitz R (editors). 5. Baskı, Philadelphia: Wolters Kluwer Health, 2014:135‐50.
  • 21. Avrupa Uyuşturucu Raporu 2019. https://doi.org/doi/10.2810/760305 (28 Haziran 2019’da ulaşıldı.)
  • 22. Kakko J, Alho H, Baldacchino A, et al. Craving in opioid use disorder: from neurobiology to clinical practice. Front Psychiatry 2019; 10: 592.
  • 23. Wang YH, Sun JF, Tao YM, et al. The role of kappa-opioid receptor activation in mediating antinociception and addiction. Acta Pharmacol Sin 2010; 31(9): 1065-1070.
  • 24. Lutz PE, Ayranci G, Chu-Sin-Chung P, et al. Distinct mu, delta, and kappa opioid receptor mechanisms underlie low sociability and depressive-like behaviors during heroin abstinence. Neuropsychopharmacology 2014; 39(11): 2694-2705.
  • 25. Yılmaz A, Can Y, Bozkurt M, Evren C. Alkol ve madde bağımlılığında remisyon ve depreşme. Psikiyatride Güncel Yaklaşımlar 2014; 6(3): 243-256.
  • 26. Kadam M, Sinha A, Nimkar S, et al. A comparative study of factors associated with relapse in alcohol dependence and opioid dependence. Indian J Psychol Med 2017; 39(5): 627-633.
  • 27. Smyth BP, Barry J, Keenan E, Ducray K. Lapse and relapse following inpatient treatment of opiate dependence. Ir Med J 2010; 103(6): 176-179.
  • 28. Xu K, Seo D, Hodgkinson C, et al. A variant on the kappa opioid receptor gene (OPRK1) is associated with stress response and related drug craving, limbic brain activation and cocaine relapse risk. Transl Psychiatry 2013; 3(8): e292.
  • 29. Strang J, Volkow ND, Degenhardt L, et al. Opioid use disorder. Nat Rev Dis Primers 2020; 6(1): 3.
  • 30. Clarke TK, Crist RC, Ang A, et al. Genetic variation in OPRD1 and the response to treatment for opioid dependence with buprenorphine in European American females. Pharmacogenomics J 2014; 14(3): 303–308.
  • 31. Evren C, Karadağ F. Alkol ve Madde Kullanım Bozuklukları Tedavi ve İzlem Klinik Protokolü. Ankara: T.C. Sağlık Bakanlığı, 2022.
  • 32. Cone EJ, Gorodetzky CW, Yousefnejad D, et al. The metabolism and excretion of buprenorphine in humans. Drug Metab Dispos 1984; 12(5): 577-581.
  • 33. Walter DS, Inturrisi CE. Absorption, distribution, metabolism, and excretion of buprenorphine in animals and humans. Cowan A, Lewis JW (editors). Buprenorphine: combatting drug abuse with a unique opioid. New York: Wiley-Liss; 1995. 113–135.
  • 34. Seguí HA, Melin K, Quiñones DS, Duconge J. A review of the pharmacogenomics of buprenorphine for the treatment of opioid use disorder. J Transl Genet Genom 2020; 4: 263–277.
  • 35. Yiannakopoulou, E. Pharmacogenomics and opioid analgesics: clinical implications. Int J Genomics 2015; 2015: 368979.
  • 36. Chawarski MC, Schottenfeld RS, O'Connor PG, Pakes J. Plasma concentrations of buprenorphine 24 to 72 hours after dosing. Drug Alcohol Depend 1999; 55(1-2): 157-163.
  • 37. Laib AK, Böttcher M, Hiemke C, Havemann-Reinecke U. Therapeutic drug-monitoring for opiate-dependent patients receiving buprenorphine for substitution. Pharmacopsychiatry 2013; 46: A32.
  • 38. Weber WW. Populations and genetic polymorphisms. Mol Diagn 1999; 4(4): 299-307.
  • 39. Roy JN, Lajoie J, Zijenah LS, et al. CYP3A5 genetic polymorphisms in different ethnic populations. Drug Metab Dispos. 2005; 33(7): 884-887.
  • 40. Sastre JA, Varela G, López M, et al. Influence of uridine diphosphate-glucuronyltransferase 2b7 (UGT2B7) variants on postoperative buprenorphine analgesia. Pain Pract 2015; 15(1): 22-30.
  • 41. Blanco F, Muriel C, Labrador J, et al. Influence of UGT2B7, CYP3A4, and OPRM1 gene polymorphisms on transdermal buprenorphine pain control in patients with critical lower limb ischemia awaiting revascularization. Pain Pract 2016; 16(7): 842-849.
  • 42. Taqi MM, Faisal M, Zaman H. OPRM1 A118G polymorphisms and its role in opioid addiction: implication on severity and treatment approaches. Pharmgenomics Pers Med 2019; 12: 361-368.
  • 43. Beer B, Erb R, Pavlic M, et al. Association of polymorphisms in pharmacogenetic candidate genes (OPRD1, GAL, ABCB1, OPRM1) with opioid dependence in European population: a case-control study. PLoS One 2013; 8(9): e75359.
  • 44. Crist RC, Doyle GA, Nelson EC, et al. A polymorphism in the OPRM1 3'-untranslated region is associated with methadone efficacy in treating opioid dependence. Pharmacogenomics J 2018; 18(1): 173-179.
  • 45. Crist RC, Phillips KA, Furnari MA, et al. Replication of the pharmacogenetic effect of rs678849 on buprenorphine efficacy in African-Americans with opioid use disorder. Pharmacogenomics J 2019; 19(3): 260-268.
  • 46. Kranzler HR, Lynch KG, Crist RC, et al. A delta-opioid receptor gene polymorphism moderates the therapeutic response to extended-release buprenorphine in opioid use disorder. Int J Neuropsychopharmacol 2021; 24(2): 89-96.
  • 47. Gerra G, Somaini L, Leonardi C, et al. Association between gene variants and response to buprenorphine maintenance treatment. Psychiatry Res 2014; 215(1): 202-207.
  • 48. Picard N, Cresteil T, Djebli N, Marquet P. In vitro metabolism study of buprenorphine: evidence for new metabolic pathways. Drug Metab Dispos 2005; 33: 689-695.
  • 49. Liao MZ, Gao C, Shireman LM, et al. P-gp/ABCB1 exerts differential impacts on brain and fetal exposure to norbuprenorphine. Pharmacol Res 2017; 119: 61-71.
Toplam 49 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Psikiyatri
Bölüm Derleme
Yazarlar

Dilek Kaya Akyüzlü 0000-0002-3305-0587

Erken Görünüm Tarihi 29 Ocak 2023
Yayımlanma Tarihi 30 Eylül 2023
Kabul Tarihi 11 Aralık 2022
Yayımlandığı Sayı Yıl 2023 Cilt: 24 Sayı: 3

Kaynak Göster

AMA Kaya Akyüzlü D. Buprenorfin Farmakokinetiğinde ve Farmakodinamiğinde Rol Oynayan Gen Polimorfizmleri: Genel Bakış. Bağımlılık Dergisi. Eylül 2023;24(3):391-401. doi:10.51982/bagimli.1203151

Bağımlılık Dergisi - Journal of Dependence