CYP3A4*18A、CYP3A4*18B和MDR1 C3435T基因多态性对阿托伐他汀血药浓度及疗效的影响

刘亦伟,林翠鸿,王长连,蔡斌,柯蒙,黄品芳

中国药学杂志 ›› 2016, Vol. 51 ›› Issue (19) : 1682-1689.

PDF(1404 KB)
PDF(1404 KB)
中国药学杂志 ›› 2016, Vol. 51 ›› Issue (19) : 1682-1689. DOI: 10.11669/cpj.2016.19.013
论著

CYP3A4*18A、CYP3A4*18B和MDR1 C3435T基因多态性对阿托伐他汀血药浓度及疗效的影响

  • 刘亦伟a,林翠鸿a,王长连a,蔡斌b,柯蒙a,黄品芳a*
作者信息 +

The Effects of CYP3A4*18A,CYP3A4*18B and MDR1 C3435T Polymorphisms on Plasma Concentration and Efficacy of Atorvastatin

  • LIU Yi-weia, LIN Cui-honga, WANG Chang-liana, CAI Binb, KE Menga, HUANG Pin-fanga*
Author information +
文章历史 +

摘要

目的 探讨高脂血症患者CYP3A4*18A、*18B和MDR1 C3435T基因多态性对阿托伐他汀血药浓度、调脂疗效的影响。方法 115例福建籍汉族高脂血症患者以聚合酶链反应-限制性片段长度多态性法(polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)进行基因分型,HPLC-UV检测阿托伐他汀稳态血药谷浓度,均相酶法监测治疗前、用药1个月后血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、甘油三酯(TG)水平。用SPSS13.0软件以ANOVA方差分析高脂血症患者基因型与调脂疗效、血药浓度之间的关系。结果 115例高脂血症患者,CYP3A4*18A、*18B的突变频率分别为3.48%和23.48%,MDR1 C3435T突变率为31.74%,三基因位点SNPs分布与文献报道的国人正常人群无显著性差异(P>0.05);CYP3A4*18A和MDR1 C3435T各基因型患者ATV血药浓度组间及组内差异均无统计学意义(P>0.05)。CYP3A4*18B基因突变纯合子(AA)组患者ATV血药浓度显著高于突变杂合子(GA)组和野生型纯合子(GG)组(P=0.016)。CYP3A4*18A、MDR1 C3435T不同基因型患者的调脂效率无显著性差异(P>0.05),CYP3A4*18B基因的AA组患者TC调脂效果显著优于GA组和GG组患者(P=0.02);LDL-C变化率三基因型组间均有显著差异,依次为AA组>GA组>GG组(P=0.01),对TG和HDL-C的调节作用3种基因型患者无显著性差异(P>0.05)。治疗前后,TC的变化率与血药浓度呈显著性相关(P=0.031),而其余3种脂质变化率与血药浓度相关性无统计学意义(P>0.05)。结论 MDR1 C3435T与CYP3A4*18A基因SNPs(single nucleotide polymorphisms),不影响ATV血药浓度及其疗效。携带CYP3A4*18B基因的患者接受ATV治疗时,比未携带者血药浓度高,调脂疗效更显著。

Abstract

OBJECTIVE To investigate the interindividual variabilities of plasma concentration and lipid-regulating efficacy of atorvastatin in patients with hyperlipidemia through the genotyping of CYP3A4*18A, *18B and MDR1 C3435T genes.METHODS One hundred and fifteen Chinese Han population with hyperlipidemia were genotyped by the PCR-RFLP (restriction fragment length polymorphism).The steady-state plasma trough concentrations of atorvastatin were measured by high performance liquid chromatography (HPLC)-UV.The levels of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were monitored by the homogeneous enzyme method before treatment and 1 month after medication.RESULTS The mutation frequencies of CYP3A4*18A,*18B and MDR1 C3435T were 3.48%,23.48% and 31.74% respectively.It shows no statistically significant difference for the SNPs frequencies between the normal population reported and patients selected.Patients with CYP3A4*18B homozygous mutant (AA) showed a significantly higher plasma concentration of ATV compared with the G/A heterozygous mutat patients or the G/G wild-type homozygous (P=0.016).However,no significant difference could be shown in the patients with CYP3A4*18A and MDR1 C3435T genotypes(P>0.05).Neither CYP3A4*18A nor MDR1 C3435T could be shown a significant difference in the lipid lowering efficiency(P>0.05).Patients carrying the homozygous mutant (AA) of the CYP3A4*18B gene showed a significantly higher TC lipid-regulating effect compared with patients with the GA or GG genetic variant (P=0.02). The LDL-C change rates among the three genotype groups were significantly different, with AA group >GA group >GG group (P=0.01) and the regulation of TG and HDL-C for AA,GA or GG was compared without finding any significant difference (P>0.05).The TC changerates and plasma concentration were significantly correlated (P=0.031) before and after treatment,while there was no statistical significance in the correlation of the other three lipid change rates with plasma concentration (P>0.05).CONCLUSION The SNPs MDR1 C3435T and CYP3A4*18A do not affect the plasma concentration and efficacy of ATV. In ATV therapy, patients with the CYP3A4*18B gene exhibit higher plasma concentrations than the non-carriers, and the lipid-lowering efficacy was more pronounced.

关键词

阿托伐他汀 / CYP3A4*18A / CYP3A4*18B / MDR1 C3435T / 基因多态性 / 血药浓度 / 聚合酶链反应-限制性片段长度多态性法

Key words

atorvastatin / CYP3A4*18A / CYP3A4*18B / MDR1C3435T / polymorphism / plasma concentration / PCR-RFLP

引用本文

导出引用
刘亦伟,林翠鸿,王长连,蔡斌,柯蒙,黄品芳. CYP3A4*18A、CYP3A4*18B和MDR1 C3435T基因多态性对阿托伐他汀血药浓度及疗效的影响[J]. 中国药学杂志, 2016, 51(19): 1682-1689 https://doi.org/10.11669/cpj.2016.19.013
LIU Yi-wei, LIN Cui-hong, WANG Chang-lian, CAI Bin, KE Meng, HUANG Pin-fang. The Effects of CYP3A4*18A,CYP3A4*18B and MDR1 C3435T Polymorphisms on Plasma Concentration and Efficacy of Atorvastatin[J]. Chinese Pharmaceutical Journal, 2016, 51(19): 1682-1689 https://doi.org/10.11669/cpj.2016.19.013
中图分类号: R969.1   

参考文献

[1] GIBSON D M, BRON N J, RICHENS A, et al. Effect of age and gender on pharmacokinetics of atorvastatin in humans. J Clin Pharmacol, 1996, 36(3):242-246.
[2] KANE G C, LIPSKY J J. Drug-grapefruit juice interactions. Mayo Clin Proc, 2000, 75(9): 933-942.
[3] MAZZU A L, LASSETER K C, SHAMBLEN E C, et al. Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin. Clin Pharmacol Ther, 2000, 68(4):391-400.
[4] KAJINAMI K, BROUSSEAU M E, ORDOVAS J M, et al. CYP3A4 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin in primary hypercholestero lemia. Am J Cardiol, 2004, 93(1):104-107.
[5] KIVISTO K T, NIEMI M, SCHAEFFELER E, et al. Lipid-lowering response to statins is affected by CYP3A5 polymorphism. Pharmacogenetics, 2004, 14(8):523-525.
[6] MU D P, XU W R, GAO Z Y. Effect of cytochrome P450 3A4 gene polymorphisms on drug metabolism. Chin Pharm J(中国药学杂志), 2008,43(6):405-408.
[7] LIOU Y H, LIN C H T, WU Y J, et al. The high prevalence of the poor and ultrarapid metabolite alleles of CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 in Taiwanese population. J Hum Genet, 2006, 51:857-863.
[8] DAI D, TANG J, ROSE R, et al. Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther, 2001, 299(3):825-831.
[9] RUZILAWATI A B, GAN S H. CYP3A4 genetic polymorphism influences repaglinide′s pharmacokinetics. Pharmacology, 2010, 85(4):357-364.
CHAMBERS T C, POHL J, RAYNOR R L, et al. Identification of specific sites in human P-glycoprotein phosphorylated by protein kinase C . J Biol Chem, 1993, 268(7):4592-4595.
FROMM M F. Importance of P-glycoprotein for drug disposition in humans. Eur J Clin Invest, 2003, 33(2):6-9.
ZHANG Y T,ZHANG H,YANG L P, et al. Effect of polymorphisms in ABCB1 and CYP3A5 on blood concentrations of cyclosporine A in myasthenia gravis patients. Chin Pharm J(中国药学杂志), 2011,46(5):368-373.
Joint committee of institution for prevention and cure guide to Chinese dyslipidemia adult. Prevention and cure guide to Chinese dyslipidemia adult 2007. Chin J Cardiol(中华心血管病杂志), 2007, 35(5):390-419.
AMEYAW M M, REGATEIRO F, LI T, et al. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics, 2001, 11(3):217-221.
LENNERNAS H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet, 2003, 42(13): 1141-1160.
HERMANN M, ASBERG A, CHRISTENSEN H, et al. Substantially elevated levels of atorvastatin and metabolites in cyclosporinetreated renal transplant recipients. Clin Pharmacol Ther, 2004, 76(4):388-391.
JACOBSON T A. Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors . Am J Cardiol, 2004, 94(9):1140-1146.
HU Y H, HE J, CHEN G L, et al. CYP3A5*3 and CYP3A4*18 single nucleotide polymorphisms in a Chinese population. Clin Chim Acta, 2005, 353(1-2):187-192.
KANG Y S, PARK S Y, YIM C H, et al. The CYP3A4*18 genotype in the cytochrome P450 3A4 gene, a rapid metabolizer of sex steroids, is associated with low bone mineral density. Clin Pharmacol Ther, 2009, 85(3):312-318.
YAMAMOTO T, NAGAFUCHI N, OZEKI T, et al. CYP3A4*18: it is not rare allele in Japanese population. Drug Metab Pharmacokinet, 2003, 18(4):267-268.
FUKUSHIMA-UESAKA H, SAITO Y, WATANABE H, et al. Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population . Hum Mutat, 2004, 23 (1):100-107.
HU Y F, TU J H, TAN Z R, et al. Association of CYP3A4*18B polymorphisms with the pharmacokinetics of cyclosporine in healthy subjects. Xenobiotica, 2007, 37(3): 315-327.
BALRAM C, SHARMA A, SIVATHASAN C, et al. Frequency of C3435T single nucleotide MDR1 genetic polymorphism in an Asian population:phenotypic genotypic correlates. Br J Clin Pharmacol, 2003, 56(1):78-83.
SAKAEDA T, NAKAMURA T, HORINOUCHI M, et al. MDR1 genotype related pharma cokinetics of digoxin after single oral administration in healthy japanese subjects. Pharm Res, 2001, 18(10):1400-1404.
QIN Y X, LU Z C, WANG H Q, et al. Detection of MDR1(C3435T) polymorphisms in the Hans of Chinese. Anat Res(解剖学研究), 2004, 26(1):11-13.
CHEW S C, SINGH O, CHEN X, et al. The effects of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 single nucleotide polymorphismson the pharmacokinetics and pharmacodynamicsof docetaxel in nasopharyngeal carcinoma patients. Cancer Chemother Pharcol, 2011, 67(6):1471-1478.
YUAN R M, ZHANG X W, DENG Q, et al. Impact of CYP3A4*1G polymorphism on metabolism of fentanyl in Chinese patients undergoing lower abdominal surgery. Clin Chim Acta, 2011, 412(9-10):755-760.
AKBAS S H, BILGEN T, KESER I, et al. The effect of MDR1(ABCB1)polymorphism on the pharmacokinetic of tacrolimus in Turkish renaltransplant recipients . Transplantat Proc, 2006, 38 (5): 1290-1292.
TADA H, TSUCHIYA N, SATOH S, et al. Impact of CYP3A5 and MDR1(ABCB1) C3435T polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantat Proc, 2005, 37(4) :1730-1732.
PASANEN M K, FREDRIKSON H, NEUVONEN P J, et al. Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther, 2007, 82(6):726-733.
LAU Y Y, HUANG Y, FRASSETTO L, et al. Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther, 2007, 81(2): 194-204.
AGUILAR-SALINAS C A, BARRETT H, SCHONFELD G, et al. Metabolic modes of action of the stains in the hyperlipoproteinemias. Atherosclerosis, 1998, 141(2):203-207.
BERGHEANU S C, REIJMERS T, ZWINDERMAN A H, et al. Lipidomic approach to evaluate rosuvastatin and atorvastatin at various dosages:investigating differential effects among statins. Curr Med Res Opin, 2008, 24(9):2477-2487.

基金

国家自然科学基金资助项目(81171114);福建省教育厅科技项目(JA09107)
PDF(1404 KB)

Accesses

Citation

Detail

段落导航
相关文章

/