来氟米特药物代谢酶和转运体的基因组学研究进展
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摘要
来氟米特是一种用于治疗免疫系统疾病的免疫调节剂,但由于存在药物不良反应,超过50%的患者在用药1年后停用该药。目前,药物遗传学研究表明单核苷酸多态性(SNPs)对来氟米特血药浓度有一定的影响,与类风湿性关节炎(RA)患者的有效性和耐受性存在潜在相关。体外研究表明,细胞色素P450酶CYP1A2、CYP2C19和CYP3A4参与来氟米特在机体内的代谢,CYP1A2*1F等位基因可能与RA患者的来氟米特不良反应相关。此外,二氢乳清酸脱氢酶(DHODH)基因rs3213422(19C>A)的C等位基因和雌激素受体(ESR1/2)的基因多态性可能与来氟米特的不良反应和治疗效果相关。本文总结了参与来氟米特体内过程相关代谢酶及转运体的基因多态性与来氟米特及其活性代谢物特立氟胺血药浓度、临床疗效以及药物不良反应的相关性,为深入研究来氟米特临床合理用药提供参考信息。
Leflunomide is an immunomodulator used to treat diseases of the immune system. More than 50% of patients discontinued leflunomide within one year due to adverse drug reaction. Currently, pharmacogenetic studies have shown that single nucleotide polymorphisms(SNPs) have an impact on leflunomide plasma concentrations, and could be associated with efficacy and tolerability in patients with rheumatoid arthritis(RA). In vitro studies have demonstrated that cytochromes P450(CYPs), mainly CYP1 A2, CYP2 C19 and CYP3 A4, are involved in leflunomide metabolism. It was shown that CYP1 A2*1 F allele may be associated with leflunomide adverse drug reactions(ADR) in patients with RA. In addition, the C allele of dihydroorotate dehydrogenase(DHODH) gene SNP rs3213422(19 C>A) and oestrogen receptor(ESR1/2) polymorphism may be associated with leflunomide ADR and therapeutic effect. In this review, we summarized the association of the genetic polymorphisms in the metabolic enzymes and transporters involved in the metabolism and disposition of leflunomide with the active metabolite teriflunomide concentration, clinical efficacy and adverse drug reaction, which provides reference for in-depth pharmacogenomic study and clinical use of leflunomide.
Leflunomide is an immunomodulator used to treat diseases of the immune system. More than 50% of patients discontinued leflunomide within one year due to adverse drug reaction. Currently, pharmacogenetic studies have shown that single nucleotide polymorphisms(SNPs) have an impact on leflunomide plasma concentrations, and could be associated with efficacy and tolerability in patients with rheumatoid arthritis(RA). In vitro studies have demonstrated that cytochromes P450(CYPs), mainly CYP1 A2, CYP2 C19 and CYP3 A4, are involved in leflunomide metabolism. It was shown that CYP1 A2*1 F allele may be associated with leflunomide adverse drug reactions(ADR) in patients with RA. In addition, the C allele of dihydroorotate dehydrogenase(DHODH) gene SNP rs3213422(19 C>A) and oestrogen receptor(ESR1/2) polymorphism may be associated with leflunomide ADR and therapeutic effect. In this review, we summarized the association of the genetic polymorphisms in the metabolic enzymes and transporters involved in the metabolism and disposition of leflunomide with the active metabolite teriflunomide concentration, clinical efficacy and adverse drug reaction, which provides reference for in-depth pharmacogenomic study and clinical use of leflunomide.
引文
[1] Fragoso YD, Brooks JB. Leflunomide and teriflunomide: altering the metabolism of pyrimidines for the treatment of autoimmune diseases [J]. Expert Rev Clin Pharmacol, 2015, 8(3):315-320.
[2] Wu GC, Xu XD, Huang Q, et al. Leflunomide: friend or foe for systemic lupus erythematosus? [J]. Rheumatol Int, 2013, 33(2):273-276.
[3] Bae J, Park JW. Topical delivery of leflunomide for rheumatoid arthritis treatment: evaluation of local tissue deposition of teriflunomide and its anti-inflammatory effects in an arthritis rat model [J]. Drug Dev Ind Pharm, 2016, 42(2):254-262.
[4] Bar-Or A, Pachner A, Menguy-Vacheron F, et al. Teriflunomide and its mechanism of action in multiple sclerosis [J]. Drugs, 2014, 74(6):659-674.
[5] Bohanec Grabar P, Grabnar I, Rozman B, et al. Investigation of the influence of CYP1A2 and CYP2C19 genetic polymorphism on 2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide (A77 1726) pharmacokinetics in leflunomide-treated patients with rheumatoid arthritis [J]. Drug Metab Dispos, 2009, 37(10):2061-2068.
[6] Alcorn N, Saunders S, Madhok R. Benefit-risk assessment of leflunomide: an appraisal of leflunomide in rheumatoid arthritis 10 years after licensing [J]. Drug Saf, 2009, 32(12):1123-1134.
[7] Bilasy SE, Essawy SS, Mandour MF, et al. Myelosuppressive and hepatotoxic potential of leflunomide and methotrexate combination in a rat model of rheumatoid arthritis [J]. Pharmacol Rep, 2015, 67(1):102-114.
[8] Bahr HI, Toraih EA, Mohammed EA, et al. Chemopreventive effect of leflunomide against Ehrlich's solid tumor grown in mice: Effect on EGF and EGFR expression and tumor proliferation [J]. Life Sci, 2015, 141:193-201.
[9] Rozman B. Clinical pharmacokinetics of leflunomide [J]. Clin Pharmacokinet, 2002, 41(6):421-430.
[10] Duquette A, Frenette AJ, Dore M. Chronic Diarrhea Associated with High Teriflunomide Blood Concentration [J]. Rheumatol Ther, 2016, 3(1):179-185.
[11] Peng J, Tan S, Zhou H, et al. Pharmacogenomics of warfarin and its personalized treatment [J]. Chinese Pharmacological Bulletin(中国药理学通报), 2013, 29(2):169-172.
[12] Stejskalova L, Dvorak Z, Pavek P. Endogenous and exogenous ligands of aryl hydrocarbon receptor: current state of art [J]. Curr Drug Metab, 2011, 12(2):198-212.
[13] Nelson DR, Zeldin DC, Hoffman SM, et al. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants [J]. Pharmacogenetics, 2004, 14(1):1-18.
[14] Aklillu E, Carrillo JA, Makonnen E, et al. Genetic polymorphism of CYP1A2 in Ethiopians affecting induction and expression: characterization of novel haplotypes with single-nucleotide polymorphisms in intron 1 [J]. Mol Pharmacol, 2003, 64(3):659-669.
[15] Sachse C, Brockmoller J, Bauer S, et al. Functional significance of a C-->A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine [J]. Br J Clin Pharmacol, 1999, 47(4):445-449.
[16] Patel A, Zhang S, Paramahamsa M, et al. Leflunomide Induces Pulmonary and Hepatic CYP1A Enzymes via Aryl Hydrocarbon Receptor [J]. Drug Metab Dispos, 2015, 43(12):1966-1970.
[17] Hopkins AM, Wiese MD, Proudman SM, et al. Genetic polymorphism of CYP1A2 but not total or free teriflunomide concentrations is associated with leflunomide cessation in rheumatoid arthritis [J]. Br J Clin Pharmacol, 2016, 81(1):113-123.
[18] Wiese MD, Schnabl M, O'Doherty C, et al. Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis [J]. Arthritis Res Ther, 2012, 14(4):R163.
[19] Chonlahan J, Halloran MA, Hammonds A. Leflunomide and warfarin interaction: case report and review of the literature [J]. Pharmacotherapy, 2006, 26(6):868-871.
[20] Sevilla-Mantilla C, Ortega L, Agundez JA, et al. Leflunomide-induced acute hepatitis [J]. Dig Liver Dis, 2004, 36(1):82-84.
[21] Bohanec Grabar P, Rozman B, Tomsic M, et al. Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients [J]. Eur J Clin Pharmacol, 2008, 64(9):871-876.
[22] Genelex. Cytochrome P450 2C19 Genotyping[EB/OL]. 2016. http://genelex.com/pharmacogenetic-tests/cyp2c19/
[23] Yin SJ, Ni YB, Wang SM, et al. Differences in genotype and allele frequency distributions of polymorphic drug metabolizing enzymes CYP2C19 and CYP2D6 in mainland Chinese Mongolian, Hui and Han populations [J]. J Clin Pharm Ther, 2012, 37(3):364-9.
[24] Russo PA, Wiese MD, Smith MD, et al. Leflunomide for inflammatory arthritis in end-stage renal disease on peritoneal dialysis: a pharmacokinetic and pharmacogenetic study [J]. Ann Pharmacother, 2013, 47(3):e15.
[25] Hopkins AM, Wiese MD, Proudman SM, et al. Semiphysiologically Based Pharmacokinetic Model of Leflunomide Disposition in Rheumatoid Arthritis Patients [J]. CPT Pharmacometrics Syst Pharmacol, 2015, 4(6):362-371.
[26] Ng JCY, Leung M, Wright AJ, et al. Clinical Pharmacokinetic Monitoring of Leflunomide in Renal Transplant Recipients with BK Virus Reactivation: A Review of the Literature [J]. Clin Pharmacokinet, 2017, 56(9):1015-1031.
[27] Nebert DW, Wikvall K, Miller WL. Human cytochromes P450 in health and disease [J]. Philos Trans R Soc Lond B Biol Sci, 2013, 368(1612):20120431.
[28] Kalgutkar AS, Nguyen HT, Vaz AD, et al. In vitro metabolism studies on the isoxazole ring scission in the anti-inflammatory agent lefluonomide to its active alpha-cyanoenol metabolite A771726: mechanistic similarities with the cytochrome P450-catalyzed dehydration of aldoximes [J]. Drug Metab Dispos, 2003, 31(10):1240-1250.
[29] Konig J, Muller F, Fromm MF. Transporters and drug-drug interactions: important determinants of drug disposition and effects [J]. Pharmacol Rev, 2013, 65(3):944-966.
[30] Kim KA, Joo HJ, Park JY. Effect of ABCG2 genotypes on the pharmacokinetics of A771726, an active metabolite of prodrug leflunomide, and association of A771726 exposure with serum uric acid level [J]. Eur J Clin Pharmacol, 2011, 67(2):129-134.
[31] van der Heijden JW, Oerlemans R, Tak PP, et al. Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide [J]. Arthritis Rheum, 2009, 60(3):669-677.
[32] Pawlik A, Herczynska M, Kurzawski M, et al. The effect of exon (19C>A) dihydroorotate dehydrogenase gene polymorphism on rheumatoid arthritis treatment with leflunomide [J]. Pharmacogenomics, 2009, 10(2):303-309.
[33] O'Doherty C, Schnabl M, Spargo L, et al. Association of DHODH haplotype variants and response to leflunomide treatment in rheumatoid arthritis [J]. Pharmacogenomics, 2012, 13(12):1427-1434.
[34] Sokka T, Toloza S, Cutolo M, et al. Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA study [J]. Arthritis Res Ther, 2009, 11(1):R7.
[35] Dziedziejko V, Kurzawski M, Safranow K, et al. The effect of ESR1 and ESR2 gene polymorphisms on the outcome of rheumatoid arthritis treatment with leflunomide [J]. Pharmacogenomics, 2011, 12(1):41-47.
[36] Pawlik A, Herczynska M, Kurzawski M, et al. IL-1beta, IL-6, and TNF gene polymorphisms do not affect the treatment outcome of rheumatoid arthritis patients with leflunomide [J]. Pharmacol Rep, 2009, 61(2):281-287.
[37] Dziedziejko V, Kurzawski M, Safranow K, et al. Lack of association between CAG repeat polymorphism in the androgen receptor gene and the outcome of rheumatoid arthritis treatment with leflunomide [J]. Eur J Clin Pharmacol, 2012, 68(4):371-377.
[38] Hopkins AM, O'Doherty CE, Foster DJ, et al. The rheumatoid arthritis susceptibility polymorphism PTPN22 C1858T is not associated with leflunomide response or toxicity [J]. J Clin Pharm Ther, 2014, 39(5):555-560.
[39] Ruiz-Padilla AJ, Gamez-Nava JI, Saldana-Cruz AM, et al. The-174G/C Interleukin-6 Gene Promoter Polymorphism as a Genetic Marker of Differences in Therapeutic Response to Methotrexate and Leflunomide in Rheumatoid Arthritis [J]. Biomed Res Int, 2016, 2016:4193538.
[2] Wu GC, Xu XD, Huang Q, et al. Leflunomide: friend or foe for systemic lupus erythematosus? [J]. Rheumatol Int, 2013, 33(2):273-276.
[3] Bae J, Park JW. Topical delivery of leflunomide for rheumatoid arthritis treatment: evaluation of local tissue deposition of teriflunomide and its anti-inflammatory effects in an arthritis rat model [J]. Drug Dev Ind Pharm, 2016, 42(2):254-262.
[4] Bar-Or A, Pachner A, Menguy-Vacheron F, et al. Teriflunomide and its mechanism of action in multiple sclerosis [J]. Drugs, 2014, 74(6):659-674.
[5] Bohanec Grabar P, Grabnar I, Rozman B, et al. Investigation of the influence of CYP1A2 and CYP2C19 genetic polymorphism on 2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide (A77 1726) pharmacokinetics in leflunomide-treated patients with rheumatoid arthritis [J]. Drug Metab Dispos, 2009, 37(10):2061-2068.
[6] Alcorn N, Saunders S, Madhok R. Benefit-risk assessment of leflunomide: an appraisal of leflunomide in rheumatoid arthritis 10 years after licensing [J]. Drug Saf, 2009, 32(12):1123-1134.
[7] Bilasy SE, Essawy SS, Mandour MF, et al. Myelosuppressive and hepatotoxic potential of leflunomide and methotrexate combination in a rat model of rheumatoid arthritis [J]. Pharmacol Rep, 2015, 67(1):102-114.
[8] Bahr HI, Toraih EA, Mohammed EA, et al. Chemopreventive effect of leflunomide against Ehrlich's solid tumor grown in mice: Effect on EGF and EGFR expression and tumor proliferation [J]. Life Sci, 2015, 141:193-201.
[9] Rozman B. Clinical pharmacokinetics of leflunomide [J]. Clin Pharmacokinet, 2002, 41(6):421-430.
[10] Duquette A, Frenette AJ, Dore M. Chronic Diarrhea Associated with High Teriflunomide Blood Concentration [J]. Rheumatol Ther, 2016, 3(1):179-185.
[11] Peng J, Tan S, Zhou H, et al. Pharmacogenomics of warfarin and its personalized treatment [J]. Chinese Pharmacological Bulletin(中国药理学通报), 2013, 29(2):169-172.
[12] Stejskalova L, Dvorak Z, Pavek P. Endogenous and exogenous ligands of aryl hydrocarbon receptor: current state of art [J]. Curr Drug Metab, 2011, 12(2):198-212.
[13] Nelson DR, Zeldin DC, Hoffman SM, et al. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants [J]. Pharmacogenetics, 2004, 14(1):1-18.
[14] Aklillu E, Carrillo JA, Makonnen E, et al. Genetic polymorphism of CYP1A2 in Ethiopians affecting induction and expression: characterization of novel haplotypes with single-nucleotide polymorphisms in intron 1 [J]. Mol Pharmacol, 2003, 64(3):659-669.
[15] Sachse C, Brockmoller J, Bauer S, et al. Functional significance of a C-->A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine [J]. Br J Clin Pharmacol, 1999, 47(4):445-449.
[16] Patel A, Zhang S, Paramahamsa M, et al. Leflunomide Induces Pulmonary and Hepatic CYP1A Enzymes via Aryl Hydrocarbon Receptor [J]. Drug Metab Dispos, 2015, 43(12):1966-1970.
[17] Hopkins AM, Wiese MD, Proudman SM, et al. Genetic polymorphism of CYP1A2 but not total or free teriflunomide concentrations is associated with leflunomide cessation in rheumatoid arthritis [J]. Br J Clin Pharmacol, 2016, 81(1):113-123.
[18] Wiese MD, Schnabl M, O'Doherty C, et al. Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis [J]. Arthritis Res Ther, 2012, 14(4):R163.
[19] Chonlahan J, Halloran MA, Hammonds A. Leflunomide and warfarin interaction: case report and review of the literature [J]. Pharmacotherapy, 2006, 26(6):868-871.
[20] Sevilla-Mantilla C, Ortega L, Agundez JA, et al. Leflunomide-induced acute hepatitis [J]. Dig Liver Dis, 2004, 36(1):82-84.
[21] Bohanec Grabar P, Rozman B, Tomsic M, et al. Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients [J]. Eur J Clin Pharmacol, 2008, 64(9):871-876.
[22] Genelex. Cytochrome P450 2C19 Genotyping[EB/OL]. 2016. http://genelex.com/pharmacogenetic-tests/cyp2c19/
[23] Yin SJ, Ni YB, Wang SM, et al. Differences in genotype and allele frequency distributions of polymorphic drug metabolizing enzymes CYP2C19 and CYP2D6 in mainland Chinese Mongolian, Hui and Han populations [J]. J Clin Pharm Ther, 2012, 37(3):364-9.
[24] Russo PA, Wiese MD, Smith MD, et al. Leflunomide for inflammatory arthritis in end-stage renal disease on peritoneal dialysis: a pharmacokinetic and pharmacogenetic study [J]. Ann Pharmacother, 2013, 47(3):e15.
[25] Hopkins AM, Wiese MD, Proudman SM, et al. Semiphysiologically Based Pharmacokinetic Model of Leflunomide Disposition in Rheumatoid Arthritis Patients [J]. CPT Pharmacometrics Syst Pharmacol, 2015, 4(6):362-371.
[26] Ng JCY, Leung M, Wright AJ, et al. Clinical Pharmacokinetic Monitoring of Leflunomide in Renal Transplant Recipients with BK Virus Reactivation: A Review of the Literature [J]. Clin Pharmacokinet, 2017, 56(9):1015-1031.
[27] Nebert DW, Wikvall K, Miller WL. Human cytochromes P450 in health and disease [J]. Philos Trans R Soc Lond B Biol Sci, 2013, 368(1612):20120431.
[28] Kalgutkar AS, Nguyen HT, Vaz AD, et al. In vitro metabolism studies on the isoxazole ring scission in the anti-inflammatory agent lefluonomide to its active alpha-cyanoenol metabolite A771726: mechanistic similarities with the cytochrome P450-catalyzed dehydration of aldoximes [J]. Drug Metab Dispos, 2003, 31(10):1240-1250.
[29] Konig J, Muller F, Fromm MF. Transporters and drug-drug interactions: important determinants of drug disposition and effects [J]. Pharmacol Rev, 2013, 65(3):944-966.
[30] Kim KA, Joo HJ, Park JY. Effect of ABCG2 genotypes on the pharmacokinetics of A771726, an active metabolite of prodrug leflunomide, and association of A771726 exposure with serum uric acid level [J]. Eur J Clin Pharmacol, 2011, 67(2):129-134.
[31] van der Heijden JW, Oerlemans R, Tak PP, et al. Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide [J]. Arthritis Rheum, 2009, 60(3):669-677.
[32] Pawlik A, Herczynska M, Kurzawski M, et al. The effect of exon (19C>A) dihydroorotate dehydrogenase gene polymorphism on rheumatoid arthritis treatment with leflunomide [J]. Pharmacogenomics, 2009, 10(2):303-309.
[33] O'Doherty C, Schnabl M, Spargo L, et al. Association of DHODH haplotype variants and response to leflunomide treatment in rheumatoid arthritis [J]. Pharmacogenomics, 2012, 13(12):1427-1434.
[34] Sokka T, Toloza S, Cutolo M, et al. Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA study [J]. Arthritis Res Ther, 2009, 11(1):R7.
[35] Dziedziejko V, Kurzawski M, Safranow K, et al. The effect of ESR1 and ESR2 gene polymorphisms on the outcome of rheumatoid arthritis treatment with leflunomide [J]. Pharmacogenomics, 2011, 12(1):41-47.
[36] Pawlik A, Herczynska M, Kurzawski M, et al. IL-1beta, IL-6, and TNF gene polymorphisms do not affect the treatment outcome of rheumatoid arthritis patients with leflunomide [J]. Pharmacol Rep, 2009, 61(2):281-287.
[37] Dziedziejko V, Kurzawski M, Safranow K, et al. Lack of association between CAG repeat polymorphism in the androgen receptor gene and the outcome of rheumatoid arthritis treatment with leflunomide [J]. Eur J Clin Pharmacol, 2012, 68(4):371-377.
[38] Hopkins AM, O'Doherty CE, Foster DJ, et al. The rheumatoid arthritis susceptibility polymorphism PTPN22 C1858T is not associated with leflunomide response or toxicity [J]. J Clin Pharm Ther, 2014, 39(5):555-560.
[39] Ruiz-Padilla AJ, Gamez-Nava JI, Saldana-Cruz AM, et al. The-174G/C Interleukin-6 Gene Promoter Polymorphism as a Genetic Marker of Differences in Therapeutic Response to Methotrexate and Leflunomide in Rheumatoid Arthritis [J]. Biomed Res Int, 2016, 2016:4193538.