CYP2D6*10对冠心病患者美托洛尔谷浓度和血压心率的影响
|
摘要
目的探讨CYP2D6*10(c.100 C>T)对冠心病患者血浆中美托洛尔及代谢物α-羟化美托洛尔谷浓度和血压心率的影响。方法将患者分成服用美托洛尔片(n=128)和美托洛尔缓释片(n=126)两组,用Taqman实时荧光定量PCR对CYP2D6*10进行基因分型,UPLC-MS/MS测定美托洛尔和α-羟化美托洛尔的谷浓度,分别比较两组患者中不同CYP2D6*10基因型患者的美托洛尔和α-羟化美托洛尔的剂量校正浓度(C/D)的差异。记录患者美托洛尔达稳态时的静息血压和心率,比较两组患者中不同基因型患者之间血压和心率的差异。结果服用美托洛尔缓释片的患者中,α-羟化美托洛尔谷浓度与收缩压相关(P=0.0204)。CYP2D6*10慢代谢型对两组患者的美托洛尔和α-羟化美托洛尔浓度均有显著影响(P<0.01),两组患者中TT型较CC型和CT型患者美托洛尔C/D高(均P<0.01);与CT型相比,TT型患者α-羟化美托洛尔C/D较低(P<0.01)。服用美托洛尔缓释片的患者中,与CC型相比,CT型(P=0.0281)和TT型(P=0.0196)患者舒张压较低,而两组患者中不同基因型患者之间收缩压和心率均无统计学差异。结论 CYP2D6*10T等位基因突变可使冠心病患者美托洛尔代谢减慢,血浆中美托洛尔浓度增加而α-羟化美托洛尔浓度和舒张压降低,CYP2D6*10对患者美托洛尔达稳态时的静息收缩压和心率无显著影响。
Objective To study the effect of CYP2 D6*10(c.100 C>T) on plasma trough concentrations of metoprolol and its metabolite α-hydroxy metoprolol, blood pressure and heart rate in patients with coronary artery disease. Methods The patients with coronary artery disease taking metoprolol tablets(n=128) and those taking metoprolol sustained-release tablets(n=126) were genotyped for CYP2 D6*10 using Taqman real-time quantitative PCR. The trough concentrations of metoprolol and α-hydroxy metoprolol were determined with UPLC-MS/MS, and the dose-normalized concentrations(C/D) were compared among the patients with different CYP2 D6*10 genotypes in both groups. Resting blood pressure and heart rate were recorded in all the patients when the concentration of metoprolol reached the steady state and were compared among the patients with different genotypes. Results In patients taking metoprolol sustained-release tablets, the plasma trough concentration of α-hydroxy metoprolol was significantly associated with the systolic blood pressure(P=0.0204). The CYP2 D6*10 poor metabolizers showed a significant association with the C/D of metoprolol and α-hydroxy metoprolol(P<0.01) in patients receiving metoprolol in both formulations, and in both groups, the C/D of metoprolol was significantly higher in the patients with a TT genotype than in those with a CC or CT genotype(P<0.01); compared with those with the CT genotype, the patients with the TT genotype had a significantly lower C/D of α-hydroxy metoprolol(P<0.01). In patients taking metoprolol sustained-release tablets, those with the CT(P=0.0281) and TT(P=0.0196) genotypes had lower diastolic blood pressure than patients with the CC genotypes, but the systolic blood pressure or heart rate did not differ significantly among them.Conclusion CYP2 D6*10 T allele mutation can reduce the metabolism of metoprolol, increase the C/D of metoprolol and decrease the C/D of α-metoprolol and diastolic blood pressure in patients with coronary artery disease, but CYP2 D6*10 variation does not significantly affect systolic blood pressure or heart rate in the patients when the concentration of metoprolol reaches a steady state.
Objective To study the effect of CYP2 D6*10(c.100 C>T) on plasma trough concentrations of metoprolol and its metabolite α-hydroxy metoprolol, blood pressure and heart rate in patients with coronary artery disease. Methods The patients with coronary artery disease taking metoprolol tablets(n=128) and those taking metoprolol sustained-release tablets(n=126) were genotyped for CYP2 D6*10 using Taqman real-time quantitative PCR. The trough concentrations of metoprolol and α-hydroxy metoprolol were determined with UPLC-MS/MS, and the dose-normalized concentrations(C/D) were compared among the patients with different CYP2 D6*10 genotypes in both groups. Resting blood pressure and heart rate were recorded in all the patients when the concentration of metoprolol reached the steady state and were compared among the patients with different genotypes. Results In patients taking metoprolol sustained-release tablets, the plasma trough concentration of α-hydroxy metoprolol was significantly associated with the systolic blood pressure(P=0.0204). The CYP2 D6*10 poor metabolizers showed a significant association with the C/D of metoprolol and α-hydroxy metoprolol(P<0.01) in patients receiving metoprolol in both formulations, and in both groups, the C/D of metoprolol was significantly higher in the patients with a TT genotype than in those with a CC or CT genotype(P<0.01); compared with those with the CT genotype, the patients with the TT genotype had a significantly lower C/D of α-hydroxy metoprolol(P<0.01). In patients taking metoprolol sustained-release tablets, those with the CT(P=0.0281) and TT(P=0.0196) genotypes had lower diastolic blood pressure than patients with the CC genotypes, but the systolic blood pressure or heart rate did not differ significantly among them.Conclusion CYP2 D6*10 T allele mutation can reduce the metabolism of metoprolol, increase the C/D of metoprolol and decrease the C/D of α-metoprolol and diastolic blood pressure in patients with coronary artery disease, but CYP2 D6*10 variation does not significantly affect systolic blood pressure or heart rate in the patients when the concentration of metoprolol reaches a steady state.
引文
[1] American college of emergency physicians, society for cardiovascular angiography and interventions, O'gara PT, et al. 2013ACCF/AHA guideline for the management of ST-elevation myocardial infarction:a report of the american college of cardiology foundation/american heart association task force on practice guidelines[J]. J Am Coll Cardiol, 2013, 61(4):e78-140.
[2]国家卫生计生委合理用药专家委员会中.高血压合理用药指南[J].中国医学前沿杂志:电子版, 2015, 35(6):22-64.
[3] Li D, Dong W, Chen Y, et al. Effect of pathway training on rest heart rate and the application ofβ-blocker in coronary heart disease patients:an open-label, multi-center, prospective study[J].Zhonghua Yi Xue Za Zhi, 2015(2015):0376-2491.
[4] Herman M, Donovan J, Tran M, et al. Use of beta-blockers and effects on heart rate and blood pressure post-acute coronary syndromes:Are we on target[J]. Am Heart J, 2009, 158(3):378-85.
[5] Tendera M, Fox K, Ferrari R, et al. Inadequate heart rate control despite widespread use of beta-blockers in outpatients with stable CAD:findings from the international prospective CLARIFY registry[J]. Int J Cardio, 2014, 176(1):119-24.
[6] Balode I, Mintale I, Latkovskis G, et al. Insufficient control of heart rate in stable coronary artery disease patients in Latvia[J]. MedicinaLithuania, 2014, 50(5):295-302.
[7] Stepinska J, Marona M, Greenlaw N, et al. Heart rate and the use of beta-blockers in stable outpatients with coronary artery disease:Polish baseline results of the CLARIFY registry[J]. Kardiol Pol,2014, 72(11):1156-64.
[8] Johnson JA, Burlew BS. Metoprolol metabolism via cytochrome P4502D6 in ethnic populations[J]. Drug Metab Dispos, 1996, 24(3):350-5.
[9] Belpaire FM, Wijnant P, Temmerman A, et al. The oxidative metabolism of metoprolol in human liver microsomes:inhibition by the selective serotonin reuptake inhibitors[J]. Eur J Clin Pharmacol,1998, 54(3):261-4.
[10]Zhou Y. Ingelman-sundberg M, lauschke V. worldwide distribution of cytochrome P450 alleles:a Meta-analysis of population-scale sequencing projects[J]. Clin Pharmacol Ther, 2017, 102(4):690.
[11]Sim SC, Kacevska M, Ingelmansundberg M. Pharmacogenomics of drug-metabolizing enzymes:a recent update on clinical implications and endogenous effects[J]. Pharmacogenomics, 2012, 13(1):1-11.
[12]Blake CM, Kharasch ED, Schwab M, et al. A Meta-analysis of CYP2D6 metabolizer phenotype and metoprolol pharmacokinetics[J]. Clin Pharmacol Ther, 2013, 94(3):394-9.
[13]Jy B, Kim YH, Lee CM, et al. CYP2D6 allele frequencies in korean population, comparison with east asian, caucasian and african populations, and the comparison of metabolic activity of CYP2D6genotypes[J]. Arch Pharm Res, 2018, 41(9):921-30.
[14]Gaedigk A. Complexities of CYP2D6 gene analysis and interpretation[J]. Int Rev Psychiatry, 2013, 25(5):534-53.
[15]Batty JA, Hall AS, White HL, et al. An investigation of CYP2D6genotype and response to metoprolol CR/XL during dose titration in patients with heart failure:a MERIT-HF substudy[J]. Clin Pharmacol Ther, 2014, 95(3):321-30.
[16]Hamadeh IS, Langaee TY, Dwivedi R, et al. Impact of CYP2D6polymorphisms on clinical efficacy&tolerability of metoprolol tartrate[J]. Clin Pharmacol Ther, 2014, 96(2):175-81.
[17]Li SC, Lin H, Sun WH, et al. A meta-analysis of the effect of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of metoprolol[J]. Int J Clin Pharmacol Ther, 2017, 55(6):483-92.
[18]Wu DC, Li GY, Deng MQ, et al. Associations between ADRB1 and CYP2D6 gene polymorphisms and the response to-blocker therapy in hypertension[J]. J Int Med Res, 2015, 43(3):424-34.
[19]Gao X, Wang H, Chen H. Impact of CYP2D6 and ADRB1polymorphisms on heart rate of post-PCI patients treated with metoprolol[J]. Pharmacogenomics, 2017, 11(2):10.
[20]白雪,朱茜,李汉平,等.超高效液相色谱-质谱联用法同时测定人血浆中美托洛尔及其代谢物的浓度[J].中国临床药理学杂志, 2018(15):1001-6821.
[21]Wu CX, Peng XW, Fan WD. Pharmacokinetic-pharmacodynamic smodeling antihypertensive effect of metoprolol and irbesartan[J].Chin J General Practice, 2016, 12(6):1674-4152.
[22]Lymperopoulos A, Mccrink KA, Brill A. Impact of CYP2D6 genetic variation on the response of the cardiovascular patient to carvedilol and metoprolol[J]. Curr Drug Metab, 2016, 17(1):30-6.
[23]董天崴,王爽,杨军,等. CYP2D6基因多态性与药物基因组学研究的进展[J].心血管康复医学杂志, 2014(3):343-6.
[24]Bagheri A, Kamalidehghan B, Haghshenas M, et al. Prevalence of the CYP2D6*10(C100T),*4(G1846A), and*14(G1758A)alleles among Iranians of different ethnicities[J]. Drug Des Devel Ther,2015, 13(9):2627-34.
[25]Bae SH, Lee JK, Cho DY, et al. Simultaneous determination of metoprolol and its metabolites, alpha-hydroxymetoprolol and Odesmethylmetoprolol, in human plasma by liquid chromatography with tandem mass spectrometry:Application to the pharmacokinetics of metoprolol associated with CYP2D6 genotypes[J]. J Sep Sci, 2014, 37(11):1256-64.
[26]Lewington S, Lacey B, Clarke R, et al. The burden of hypertension and associated risk for cardiovascular mortality in China[J]. JAMA Intern Med, 2016, 176(4):524-32.
[27]Khan H, Kunutsor S, Kalogeropoulos AP, et al. Resting heart rate and risk of incident heart failure:three prospective cohort studies and a systematic meta-analysis[J]. J Am Heart Assoc, 2015, 4(1):791-8.
[28]Wang SL, Wang CL, Wang PL, et al. Resting heart rate associates with one-year risk of major adverse cardiovascular events in patients with acute coronary syndrome after percutaneous coronary intervention[J]. Exp Biol Med, 2016, 241(5):478-84.
[29]Ayyappadihas R, Dhanalekshmi U, Jestin H. CYP 2D6*4 polymorphism and interindividual response variation to metoprolol in stage1 hypertensive patients:no association in a rural Indian population[J]. Turk J Med Sci, 2015, 45(2):10.
[30]Chen LP, Xiao T, Chen LL, et al. The association of ADRB1 and CYP2D6 polymorphisms with antihypertensive effects and analysis of their contribution to hypertension risk[J]. Am J Med Sci, 2018,355(3):235-9.
[31]Wang H, Liu JL, Liu K, et al. Beta 1-adrenoceptor gene Arg389Gly polymorphism and essential hypertension risk in general population:a meta-analysis[J]. Mol Biol Rep, 2013, 40(6):4055-63.
[32]Lanfear DE, Peterson EL, Zeld N, et al. Beta blocker survival benefit in heart failure is associated with ADRB1 Ser49Gly genotype[J]. J Card Fail, 2015, 21(8, S):S50.
[2]国家卫生计生委合理用药专家委员会中.高血压合理用药指南[J].中国医学前沿杂志:电子版, 2015, 35(6):22-64.
[3] Li D, Dong W, Chen Y, et al. Effect of pathway training on rest heart rate and the application ofβ-blocker in coronary heart disease patients:an open-label, multi-center, prospective study[J].Zhonghua Yi Xue Za Zhi, 2015(2015):0376-2491.
[4] Herman M, Donovan J, Tran M, et al. Use of beta-blockers and effects on heart rate and blood pressure post-acute coronary syndromes:Are we on target[J]. Am Heart J, 2009, 158(3):378-85.
[5] Tendera M, Fox K, Ferrari R, et al. Inadequate heart rate control despite widespread use of beta-blockers in outpatients with stable CAD:findings from the international prospective CLARIFY registry[J]. Int J Cardio, 2014, 176(1):119-24.
[6] Balode I, Mintale I, Latkovskis G, et al. Insufficient control of heart rate in stable coronary artery disease patients in Latvia[J]. MedicinaLithuania, 2014, 50(5):295-302.
[7] Stepinska J, Marona M, Greenlaw N, et al. Heart rate and the use of beta-blockers in stable outpatients with coronary artery disease:Polish baseline results of the CLARIFY registry[J]. Kardiol Pol,2014, 72(11):1156-64.
[8] Johnson JA, Burlew BS. Metoprolol metabolism via cytochrome P4502D6 in ethnic populations[J]. Drug Metab Dispos, 1996, 24(3):350-5.
[9] Belpaire FM, Wijnant P, Temmerman A, et al. The oxidative metabolism of metoprolol in human liver microsomes:inhibition by the selective serotonin reuptake inhibitors[J]. Eur J Clin Pharmacol,1998, 54(3):261-4.
[10]Zhou Y. Ingelman-sundberg M, lauschke V. worldwide distribution of cytochrome P450 alleles:a Meta-analysis of population-scale sequencing projects[J]. Clin Pharmacol Ther, 2017, 102(4):690.
[11]Sim SC, Kacevska M, Ingelmansundberg M. Pharmacogenomics of drug-metabolizing enzymes:a recent update on clinical implications and endogenous effects[J]. Pharmacogenomics, 2012, 13(1):1-11.
[12]Blake CM, Kharasch ED, Schwab M, et al. A Meta-analysis of CYP2D6 metabolizer phenotype and metoprolol pharmacokinetics[J]. Clin Pharmacol Ther, 2013, 94(3):394-9.
[13]Jy B, Kim YH, Lee CM, et al. CYP2D6 allele frequencies in korean population, comparison with east asian, caucasian and african populations, and the comparison of metabolic activity of CYP2D6genotypes[J]. Arch Pharm Res, 2018, 41(9):921-30.
[14]Gaedigk A. Complexities of CYP2D6 gene analysis and interpretation[J]. Int Rev Psychiatry, 2013, 25(5):534-53.
[15]Batty JA, Hall AS, White HL, et al. An investigation of CYP2D6genotype and response to metoprolol CR/XL during dose titration in patients with heart failure:a MERIT-HF substudy[J]. Clin Pharmacol Ther, 2014, 95(3):321-30.
[16]Hamadeh IS, Langaee TY, Dwivedi R, et al. Impact of CYP2D6polymorphisms on clinical efficacy&tolerability of metoprolol tartrate[J]. Clin Pharmacol Ther, 2014, 96(2):175-81.
[17]Li SC, Lin H, Sun WH, et al. A meta-analysis of the effect of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of metoprolol[J]. Int J Clin Pharmacol Ther, 2017, 55(6):483-92.
[18]Wu DC, Li GY, Deng MQ, et al. Associations between ADRB1 and CYP2D6 gene polymorphisms and the response to-blocker therapy in hypertension[J]. J Int Med Res, 2015, 43(3):424-34.
[19]Gao X, Wang H, Chen H. Impact of CYP2D6 and ADRB1polymorphisms on heart rate of post-PCI patients treated with metoprolol[J]. Pharmacogenomics, 2017, 11(2):10.
[20]白雪,朱茜,李汉平,等.超高效液相色谱-质谱联用法同时测定人血浆中美托洛尔及其代谢物的浓度[J].中国临床药理学杂志, 2018(15):1001-6821.
[21]Wu CX, Peng XW, Fan WD. Pharmacokinetic-pharmacodynamic smodeling antihypertensive effect of metoprolol and irbesartan[J].Chin J General Practice, 2016, 12(6):1674-4152.
[22]Lymperopoulos A, Mccrink KA, Brill A. Impact of CYP2D6 genetic variation on the response of the cardiovascular patient to carvedilol and metoprolol[J]. Curr Drug Metab, 2016, 17(1):30-6.
[23]董天崴,王爽,杨军,等. CYP2D6基因多态性与药物基因组学研究的进展[J].心血管康复医学杂志, 2014(3):343-6.
[24]Bagheri A, Kamalidehghan B, Haghshenas M, et al. Prevalence of the CYP2D6*10(C100T),*4(G1846A), and*14(G1758A)alleles among Iranians of different ethnicities[J]. Drug Des Devel Ther,2015, 13(9):2627-34.
[25]Bae SH, Lee JK, Cho DY, et al. Simultaneous determination of metoprolol and its metabolites, alpha-hydroxymetoprolol and Odesmethylmetoprolol, in human plasma by liquid chromatography with tandem mass spectrometry:Application to the pharmacokinetics of metoprolol associated with CYP2D6 genotypes[J]. J Sep Sci, 2014, 37(11):1256-64.
[26]Lewington S, Lacey B, Clarke R, et al. The burden of hypertension and associated risk for cardiovascular mortality in China[J]. JAMA Intern Med, 2016, 176(4):524-32.
[27]Khan H, Kunutsor S, Kalogeropoulos AP, et al. Resting heart rate and risk of incident heart failure:three prospective cohort studies and a systematic meta-analysis[J]. J Am Heart Assoc, 2015, 4(1):791-8.
[28]Wang SL, Wang CL, Wang PL, et al. Resting heart rate associates with one-year risk of major adverse cardiovascular events in patients with acute coronary syndrome after percutaneous coronary intervention[J]. Exp Biol Med, 2016, 241(5):478-84.
[29]Ayyappadihas R, Dhanalekshmi U, Jestin H. CYP 2D6*4 polymorphism and interindividual response variation to metoprolol in stage1 hypertensive patients:no association in a rural Indian population[J]. Turk J Med Sci, 2015, 45(2):10.
[30]Chen LP, Xiao T, Chen LL, et al. The association of ADRB1 and CYP2D6 polymorphisms with antihypertensive effects and analysis of their contribution to hypertension risk[J]. Am J Med Sci, 2018,355(3):235-9.
[31]Wang H, Liu JL, Liu K, et al. Beta 1-adrenoceptor gene Arg389Gly polymorphism and essential hypertension risk in general population:a meta-analysis[J]. Mol Biol Rep, 2013, 40(6):4055-63.
[32]Lanfear DE, Peterson EL, Zeld N, et al. Beta blocker survival benefit in heart failure is associated with ADRB1 Ser49Gly genotype[J]. J Card Fail, 2015, 21(8, S):S50.