MDR1和CYP3A5基因多态性对再生障碍性贫血患者环孢菌素A血药浓度的影响
|
摘要
【目的】
探讨MDR1及CYP3A5基因多态性对再生障碍性贫血(aplasticanemia,AA)患者环孢菌素A(cyclosporine A,CsA)血药浓度的影响。
【方法】
选取达目标浓度范围[CsA谷浓度＞150ng/ml或服药后2h血药浓度＞600ng/ml]的AA患者99例,用聚合酶链反应-限制性内切酶片断长度多态性(PCR-RFLP)方法分析MDR1 C1236T、G2677T/A、C3435T和CYP3A5木3基因型。比较各基因型及单倍体型CsA剂量调整的谷浓度[谷浓度(C_0)/(剂量/体重),C_0t]和CsA剂量调整的服药后2h血药浓度[服药后2h血药浓度(C_2)/(剂量/体重),C_2t]的差异。
【结果】
MDR1 1236C等位基因频率为37.9%,MDR1 1236T等位基因频率为62.1%;MDR1 2677G、2677T和2677A等位基因频率分别为43.5%、40.8%和15.7%;MDR1 3435C和3435T等位基因频率分别为62.7%和37.3%;CYP3A5*1等位基因频率26.3%,CYP3A5*3等位基因频率73.7%。CYP3A5*3/*3基因型和CYP3A5*1/*1(或CYP3A5*1/*3)基因型C_2t中位数分别为202.59(58.25-418.28)和165.88(88.49-2.88.01)ng/ml/(mg/kg),具有显著性差异(P＜0.05),示CYP3A5*3变异型纯合子个体C_2t高于野生型纯合子和杂合子。CYP3A5*1/*1(或CYP3A5*1/*3)与CYP3A5*3/*3基因型C_0t比较,差别无统计学意义(P＞0.05)。MDR1 C1236T、G2677T/A和C3435T各基因型及单倍体型C_0t和C_2t无显著性差异(P＞0.05)。
【结论】
AA患者CYP3A5*3单核苷酸多态性影响CsA药物代谢,是造成个体CsA生物利用度变异性程度大的原因之一。与携有CYP3A5*1等位基因的AA患者相比,CYP3A5*3/*3基因型患者口服较低的CsA剂量就能达到相当的C_2水平。
Objective
The study was aimed at investigating MDR-1 and CYP3A5 genetic polymorphisms effecting on cyclosporine(CsA) blood concentrations in aplastic anemia(AA) patients.
Methods
99 AA cases,reaching the target CsA blood concentrations[CsA trough blood concentrations(C_0) more than 150ng/ml or the peak concentrations 2h after oral ingestion(C_2) more than 600ng/ml],were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for MDR1 C1236T,G2677T/A,C3435T and CYP3A5~*3. Dose-adjusted C_0 and C_2 were performed to analyze compared among the different genotype groups.
Results
Allele frequencies for C and T at position 1236 of MDR1 were 37.9% and 62.1%,respectively.For the single-nucleotide polymorphisms(SNPs) in MDR1 G2677T/A,the frequencies of the wildtype(G) and two other alleles(T/A) were found at allele frequencies of 43.5%,40.8%and 15.7%, respectively.The frequencies for C and T at position 3435 of MDR1 were 62.7%and 37.3%,respectively.For the CYP3A5 gene,the frequencies of CYP3A5~*1 and CYP3A5~*3 were 26.3%and 73.7%,respectively.The dose-adjusted C_2 in CYP3A5~*3/~*3 patients was larger than that of CYP3A5~*1/~*1 or CYP3A5~*1/~*3 patients[202.59(58.25-418.28) versus 165.88(88.49-288.01) ng/ml/(mg/kg),P＜0.05].No significant difference in cyclosporine dose-adjusted C_0 and C_2 was observed in other genotypes and haplotypes.
Conclusion
Single-nucleotide polymorphisms in CYP3A5~*3 have influence on the cyclosporine blood concentrations and be responsible,in part,for the large interindividual variability of cyclosporine pharmacokinetics in AA patient.Patients with the CYP3A5~*3/~*3 genotype require a low dose of cyclosporine to reach target C_2 levels.compared with those with the CYP3A5~*1 allele.
探讨MDR1及CYP3A5基因多态性对再生障碍性贫血(aplasticanemia,AA)患者环孢菌素A(cyclosporine A,CsA)血药浓度的影响。
【方法】
选取达目标浓度范围[CsA谷浓度＞150ng/ml或服药后2h血药浓度＞600ng/ml]的AA患者99例,用聚合酶链反应-限制性内切酶片断长度多态性(PCR-RFLP)方法分析MDR1 C1236T、G2677T/A、C3435T和CYP3A5木3基因型。比较各基因型及单倍体型CsA剂量调整的谷浓度[谷浓度(C_0)/(剂量/体重),C_0t]和CsA剂量调整的服药后2h血药浓度[服药后2h血药浓度(C_2)/(剂量/体重),C_2t]的差异。
【结果】
MDR1 1236C等位基因频率为37.9%,MDR1 1236T等位基因频率为62.1%;MDR1 2677G、2677T和2677A等位基因频率分别为43.5%、40.8%和15.7%;MDR1 3435C和3435T等位基因频率分别为62.7%和37.3%;CYP3A5*1等位基因频率26.3%,CYP3A5*3等位基因频率73.7%。CYP3A5*3/*3基因型和CYP3A5*1/*1(或CYP3A5*1/*3)基因型C_2t中位数分别为202.59(58.25-418.28)和165.88(88.49-2.88.01)ng/ml/(mg/kg),具有显著性差异(P＜0.05),示CYP3A5*3变异型纯合子个体C_2t高于野生型纯合子和杂合子。CYP3A5*1/*1(或CYP3A5*1/*3)与CYP3A5*3/*3基因型C_0t比较,差别无统计学意义(P＞0.05)。MDR1 C1236T、G2677T/A和C3435T各基因型及单倍体型C_0t和C_2t无显著性差异(P＞0.05)。
【结论】
AA患者CYP3A5*3单核苷酸多态性影响CsA药物代谢,是造成个体CsA生物利用度变异性程度大的原因之一。与携有CYP3A5*1等位基因的AA患者相比,CYP3A5*3/*3基因型患者口服较低的CsA剂量就能达到相当的C_2水平。
Objective
The study was aimed at investigating MDR-1 and CYP3A5 genetic polymorphisms effecting on cyclosporine(CsA) blood concentrations in aplastic anemia(AA) patients.
Methods
99 AA cases,reaching the target CsA blood concentrations[CsA trough blood concentrations(C_0) more than 150ng/ml or the peak concentrations 2h after oral ingestion(C_2) more than 600ng/ml],were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for MDR1 C1236T,G2677T/A,C3435T and CYP3A5~*3. Dose-adjusted C_0 and C_2 were performed to analyze compared among the different genotype groups.
Results
Allele frequencies for C and T at position 1236 of MDR1 were 37.9% and 62.1%,respectively.For the single-nucleotide polymorphisms(SNPs) in MDR1 G2677T/A,the frequencies of the wildtype(G) and two other alleles(T/A) were found at allele frequencies of 43.5%,40.8%and 15.7%, respectively.The frequencies for C and T at position 3435 of MDR1 were 62.7%and 37.3%,respectively.For the CYP3A5 gene,the frequencies of CYP3A5~*1 and CYP3A5~*3 were 26.3%and 73.7%,respectively.The dose-adjusted C_2 in CYP3A5~*3/~*3 patients was larger than that of CYP3A5~*1/~*1 or CYP3A5~*1/~*3 patients[202.59(58.25-418.28) versus 165.88(88.49-288.01) ng/ml/(mg/kg),P＜0.05].No significant difference in cyclosporine dose-adjusted C_0 and C_2 was observed in other genotypes and haplotypes.
Conclusion
Single-nucleotide polymorphisms in CYP3A5~*3 have influence on the cyclosporine blood concentrations and be responsible,in part,for the large interindividual variability of cyclosporine pharmacokinetics in AA patient.Patients with the CYP3A5~*3/~*3 genotype require a low dose of cyclosporine to reach target C_2 levels.compared with those with the CYP3A5~*1 allele.
引文
1 Kumagai N, Benedict SH, Mills GB, et al. Cyclosporin A inhibits initiation but not progression of human T cell proliferation triggered by phorbol esters and calcium ionophores. J Immunol, 1988, 141(11):3747-3752.
2 Schwab M, Eichelbaum M, Fromm MF. Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol,2003,43:285-307.
3 Hoffmeyer S, Burk O, von Richter 0, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with Pglycoprotein expression and activity in vivo. Proc Natl Acad Sci USA, 2000, 97(7):3473-3478.
4 von Ahsen N, Richter M, Grupp C, et al. No influence of the MDR-1 C3435T polymorphism or a CYP3A4 promoter polymorphism (CYP3A4-V allele) on dose-adjusted cyclosporine A trough concentrations or rejection incidence in stable renal transplant recipients. Clin Chem, 2001, 47(6): 1048-1052.
5 Chowbay B, Cumaraswany S, Cheung YB, et al. Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Pharmacogenetics, 2003, 13(2): 89-95.
6 Yates CR, Zhang W, Song P, et al. The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients. J Clin Pharmacol, 2003, 43(6): 555-564.
7 Kuzuya T, Kobayashi T, Moriyama N, et al. Amlodipine, but not MDRl polymorphisms, alters the pharmacokinetics of cyclosporine A in Japanese kidney transplant recipients. Transplantation, 2003, 76(5):865-868.
8 Anglicheau D, Thervet E, Etienne I, et al. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther, 2004, 75(5): 422-433.
9 Zheng H, Schuetz E, Zeevi A, et al. Sequential analysis of tacrolimus dosing in adult lung transplant patients with ABCB1 haplotypes. J Clin Pharmacol, 2005, 45(4): 404-410.
10 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): 100-108.
11 Xie HG, Wood AJ, Kim RB, et al. Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics, 2004, 5(3): 243-272.
12 Hu YF, Qiu W, Liu ZQ, et al. Effects of genetic polymorphisms of CYP 3A4, CYP3A5 and MDR1 on cyclosporine pharmacokingetics after renal transplantation. Clin Exp Pharmacol Physiol, 2006, 33(11):1093-1098.
13 Min DI,Ellingrod VL,Marsh S.CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects.Ther Drug Monit,2004,26(5):524-528.
14 Haufroid V,Mourad M,Van Kerckhove V,et al.The effect of CYP3A5 and MDR1(ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients.Pharmacogenetics,2004,14(3):147-154.
15 杨崇礼,邵宗鸿.再生障碍性贫血//张之南,沈悌,编著.血液病诊断及疗效标准.第三版.北京:科学出版社.2007:19-23.
16 Wasilewska A,Zalewski G,Chyczewski L,et al.MDR-1 gene polymorphisms and clinical course of steroid-responsive nephrotic syndrome in children.Pediatr Nephrol,2007,22(1):44-51.
17 van Schaik RH,van der Heiden IP,van den Anker JN,et al.CYP3A5variant allele frequencies in Dutch Caucasians.Clin Chem,2002,48(10):1668-1671.
18 岑宇翔,陆志诚,汪华侨.汉族人MDR1 C3435T基因的多态性.解剖学研究,2004,26(1):11-13.
19 Kuehl R Zhang J,Lin Y,et al.Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.Nat Genet,2001,27(4):383-391.
20 Fredericks S,Jorga A,MacPhee IA,et al.Multi-drug resistance gene-1(MDR-1) haplotypes and the CYP3A5*1 genotype have no influence on ciclosporin dose requirements as assessed by CO or C2 measurements. Clin Transplant, 2007, 21(2): 252-257.
21 Bonhomme-Faivre L, Devocelle A, Saliba F, et al. MDR-1 C3435T polymorphism influences cyclosporine a dose requirement in liver-transplant recipients.Transplantation, 2004, 78(1):21-25.
22 Foote CJ, Greer W, Kiberd B, et al. Polymorphisms of multidrug resistance gene (MDR1) and cyclosporine absorption in de novo renal transplant patients. Transplantation, 2007, 83 (10): 1380-1384.
23 Foote CJ, Greer W, Kiberd BA, et al. MDR1 C3435T polymorphisms correlate with cyclosporine levels in de novo renal recipients.Transplant Proc, 2006, 38(9): 2847-2849.
24 Tanabe M, Ieiri I, Nagata N, et al. Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-l gene.J Pharmacol Exp Ther, 2001, 297(3):1137-1143.
25 Kioka N, Tsubota J, Kakehi Y, et al. P-glycoprotein gene (MDR1) cDNA from human adrenal: normal Pglycoprotein carries Gly185 with an altered pattern of multidrug resistance. BiochemBiophys Res Commun, 1989, 162(1): 224-231.
26 Song P, Lamba JK, Zhang L, et al. G2677T and C3435T genotype and haplotype are associated with hepatic ABCB1 (MDR1) expression. J Clin Pharmacol, 2006, 46(3): 373-379. Kumagai N,Benedict SH,Mills GB,et al.Cyclosporin A inhibits initiation but not progression of human T cell proliferation triggered by phorbol esters and calcium ionophores.J Immunol,1988,141(11):3747-3752.
2 张万起,元云峰,宓怀风.亲免素结合类免疫抑制剂作用的分子机理.中国药理学与毒理学杂志,2002,16(2):155-160.
3 Su B,Jacinto E,Hibi M,et al.JNK is involved in signal integration during costimulation of T lymphocytes.Cell,1994,77(5):727-736.
4 Matsuda S,Moriguchi T,Koyasu S,et al.T lymphocyte activation signals for interleuk in production involve activation of MKK6-p38and MKK7-SAPK/JNK signaling pathways sensitive to cyclosporin A.J Biol Chem,1998,273(20):12378-12382.
5 Karin M.The regulation of AP-1 activity by mitogen activated protein kinases.J Biol Chem,1995,270(28):16483-16486.
6 Karin M,De|hase M.JNK or IKK,AP-1 or NF-kappaB,which are the targets for MEK kinase 1 action? ProcNatl Acad Sci USA,1998,95(16):9067-9069.
7 Aoyama T,Yamano S,Waxman DJ,et al.Cytochrome P-450 hPCN3,a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver,cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. J Biol Chem, 1989, 264( 18): 10388-10395.
8 Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter, Annu Rev Biochem, 1993, 62:385-427.
9 Fricker G, Drewe J, Huwyler J, et al. Relevance of p-glycoprotein for the enteral absorption of cyclosporin A: In vitro in vivo correlation. Br J Pharmacol, 1996, 118(7): 1841-1847.
10 Burton PS, Conaradi RA, Hilgers AR,et al. Evidence for a polarized efflux for peptides in the apical membrane of Caco-2 cells. Biochem Biophys Res Commun, 1993, 190(3):760-766.
11 Stieger B, Fattinger K, Madon J, et al. Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology, 2000, 118(2): 422-430.
12 Song P, Lamba JK, Zhang L, et al. G2677T and C3435T genotype and haplotype are associated with hepatic ABCB1 (MDR1) expression. J Clin Pharmacol, 2006, 46(3):373-379.
13 Nakamura T, Sakaeda T, Horinouchi M, et al. Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin Pharmacol Ther, 2002, 71(4): 297-303.
14 Hitzl M, Schaeffeler E, Hocher B,et al. Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1).Pharmacogenetics, 2004, 14(5): 309-318.
15 Kimchi-Sarfaty C, Oh JM, Kim IW, et al. A "silent" polymorphism in the MDRl gene changes substrate specificity. Science, 2007,315(5811):525-528.
16 Foote CJ, Greer W, Kiberd Bet, et al. Polymorphisms of multidrug resistance gene (MDR1) and cyclosporine absorption in de novo renal transplant patients. Transplantation, 2007 , 83(10): 1380-1384.
17 Foote CJ, Greer W, Kiberd BA, et al. MDR1 C3435T polymorphisms correlate with cyclosporine levels in de novo renal recipients.Transplant Proc, 2006, 38(9):2847-2849.
18 Anglicheau D, Thervet E, Etienne I, et al. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther, 2004, 75(5): 422-433.
19 Haufroid V, Mourad M, Van Kerckhove V, et al. The effect of CYP3A5 and MDRl (ABCBl) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics. 2004, 14(3): 145-146.
20 Mai I, Stormer E, Goldammer M, et al. MDRl haplotypes do not affect the steady-state pharmacokinetics of cyclosporine in renal transplant patients. J Clin Pharmacol, 2003, 43(10):1101-1107.
21 Bonhomme-Faivre L,Devocelle A,Saliba F,et al.MDR-1 C3435T polymorphism influences cyclosporine a dose requirement in liver-transplant recipients.Transplantation.2004,78(1):21-25.
22 Chowbay B,Cumaraswamy S,Cheung YB,et al.Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporine disposition in heart transplant recipients.Pharmacogenetics,2003,13(2):89-95.
23 张亚同,杨莉萍,邵宏,等.MDR1基因C3435T多态性对重症肌无力患者环孢素血药浓度的影响.中国临床药理学与治疗学,2005,10(2);133-136
24 Daniel F,Loriot MA,Seksik P,et al.Multidrug resistance gene-1polymorphisms and resistance to cyclosporine A in patients with steroid resistant ulcerative colitis.Inflamm Bowel Dis,2007,13(1):19-23.
25 Hu YF,Qiu W,Liu ZQ,etal.Effects of genetic polymorphisms of CYP 3A4,CYP3A5 and MDR1 on cyclosporine pharmacokingetics after renal transplantation.Clin Exp Pharmacol Physiol,2006,33(11):1093-1098.
26 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.
27 Xie HG,Wood A J,Kim RB,et al.Genetic variability in CYP3A5 and its possible consequences.Pharmacogenomics,2004,5(3):243 -272.
28 Kuehl P,Zhang J,Lin Y,et al.Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.Nat Genet,2001,27(4):383-391.
29 Langaee TY,Gong Y,Yarandi HN,et al.Association of CYP3A5polymorphisms with hypertension and antihypertensive response to verapamil.Clin Pharmacol Ther,2007,81(3):386-391.
30 Min DI,Ellingrod VL,Marsh S.CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects.Ther Drug Monit,2004,26(5):524-528.
31 Haufroid V,Mourad M,Van Kerckhove V,et al.The effect of CYP3A5 and MDR1(ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients.Pharmacogenetics,2004,14(3):147-154.
32 Wadhwa NK,Schroeder TJ,O'Flaherty E,et al.The effect of oral metoclopramide on the absorption of cyclosporine.Transplant Proc,1987,19(1 Pt 2):1730-1733.
33 孙成春,郝俊文,李香铁,等.影响环孢素A血药浓度的因素分析.现代应用药学,1995,12(2):37-38.34 Hughes CM,Swanton JG,Collier PS.The effect of three H2 receptor antagonists on the disposition of cyclosporin A in the in situ perfused rat liver model.Biopharm Drug DislSos,1995,16(9):719-733.
35 Reichenspurner H,Meiser BM,Muschiol F,et al.The influence of gastrointestinal agents on resorption and metabolism of cyclosporine after heart transplantation:experimental and clinical results.J Heart Lung Transplant,1993,12(6 Pt 1):987-992.
36 朱金照,冷恩红,陈东风.红霉素促胃动力作用的研究及临床应用.河北医科大学学报,2000,21(1):60-62
37 王开贞,徐红.红霉素的胃肠反应机制与防治研究.中国临床医生,2003,31(3):49-60.
38 Ohba M,Ohnishi N,Komada F,et al.Effect of clarithromycin on the bioavailability of cyclosporin in rats.Biol Pharm Bull,1996,19(5):733-737.
39 Sketris IS,.Wright MR,West ML.Possible role of the intestinal P-450enzyme system in a cyclosporine-clarithromycin interaction.Pharmacotherapy,1996,16(2):301-305.
40 Capone D,Aiello C,Santoro GA,et al.Drug interaction between cyclosporine and two antimicrobial agents,josamycin and rifampicin,in organ-transplanted patients.Int J Clin Pharmacol Res,1996,16(2-3):73-76.
41 McLellan.RA,Drobitch RK,Monshouwer M,et al.Fluoroquinolone antibiotics inhibit cytochrome P450-mediated microsomal drug metabolism in rat and human.Drug Metab Dispos,1996,24(10):1134-1138.
42 McLellan RA,Drobitch RK,McLellan H,et al.Norfloxacin interferes with cyclosporine disposition in pediatric patients undergoing renal transplantation.Clin Pharmacol Ther,1995,58(3):322-327.
43 Hoey LL,Lake KD.Does ciprofloxacin interact with cyclosporine?Ann Pharmacother,1994,28(1):93-96.
44 Kr(u|¨)ger HU,Schuler U,Proksch B,et al.Investigation of potential interaction of ciprofloxacin with cyclosporine in bone marrow transplant recipients.Antimicrob Agents Chemother,1990,34(6):1048-1052.
45 Campana C,Regazzi MB,Buggia I,et al.Clinically significant drug interactions with cyclosporin.An update.Clin Pharmacokinet,1996,30(2):141-179.
46 Kwan JT,Foxall PJ,Davidson DG,et al.Interaction of cyclosporin and itraconazole.Lancet,1987,2(8553):282.
47 Canafax DM,Graves NM,Hilligoss DM,et al.Increased cyclosporine levels as a result of simultaneous fluconazole and cyclosporine therapy in renal transplant recipients:a double-blind,randomized pharmacokinetic and safety study.Transplant Proc,1991,23(1 Pt 2):1041-1042.
48 闫正华,王茂义,黄猛,等.肾移植患者应用更昔洛韦后环孢菌素的药动学及生化指标的研究.西安医科大学学报,1999,20(2):42-44.
49 Hannemann J, Wunderle W, Yousif T, et al. Toxic effect of concomitant administration of cyclosporin A and acyclovir on renal function and morphology in rats. Arch Toxicol, 1997, 71(9):556-562.
50 Grino JM, Sabate I, Castelao AM, et al. Influence of diltiazem on cyclosporin clearance. Lancet, 1986, 1(8494): 1387.
51 Shennib H, Auger JL. Diltiazem improves cyclosporine dosage in cystic fibrosis lung transplant recipients . J Heart Lung Transplant,1994, 13 (2) :292-296.
52 Duvoux C, Cherqui D, Di Martino V, et al. Nicardipine as antihypertensive therapy in liver transplant recipients: results of long-term use. Hepatology, 1997, 25(2):430-433.
53 Martin JE, Daoud AJ, Schroeder TJ, et al. The clinical and economic potential of cyclosporin drug interactions. Pharmacoeconomics, 1999,15(4):317-337.
54 Islam SI, Masuda QN, Bolaji 00, et al. Possible interaction between cyclosporine and glibenclamide in posttransplant diabetic patient.Ther Drug Monit, 1996 ,18 (5) :624-626.
55 Chidester PD, Connito DJ. Interaction between glipizide and cyclosporine: report of two cases. Transplant Proc, 1993,25(2):2136-2137.
56 Carstensen H, Jacobsen N, Dieperink H. Interaction between cyclosporin A and phenobarbitone. Br J Clin Pharmacol, 1986, 21: 550-551
57 Klintmalm G,S(a|¨)we J,Ringden O,et al.Cyclosporine plasma levels in renal transplant patients.Association with renal toxicity and allograft rejection.Transplantation,1985,39(2):132-137.
58 余爱荣,吴笑春,李罄,等.联苯双酯对肾移植受者CsA全血浓度的影响及肝毒性的防护作用.中国临床药理学与治疗学杂志,2004,9(5):548-550.
59 吴家清,刘东,唐斌,等.联苯双酯对肾移植患者CsA血药浓度的影响.广东医学,2004,25(1):85-86.
60 Kaplan B,Friedman G,Jacobs M,et al.Potential interaction of troglitazone and cyclosporine.Transplantation,1998,27;65(10):1399-1400.
61 Boissonnat P,de Lorgeril M,Perroux V,et al.A drug interaction study between ticlopodine and cyclosporin in heart transplant recipients.Eur J Clin Pharmacol,1997,53(1):39-45.
1 Amiel A,Yukla M,Yogev S,et al.Deletion of 5q31 and 7q31 in patients with stable melphalan-treated multiple myeloma.Cancer Genet Cytogenet,2004,152:84-87.
2 Ishiia Y,Hsiaoa HH,Sashidaa G,et al.Derivative(1;7)(q10;p10) in multiple myeloma.A sign of therapy-related hidden myelodysplastic syndrome.Cancer Genetics and Cytogenetics,2006,167:131-137.
3 Mauritzson N,Albin M,Rylander L,et al.Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976-1993 and on 5098unselected cases reported in the literature 1974-2001.Leukemia,2002,16:2366-23.78.
4 Rodjer S,Swolin B,Weinfeld A,et al.Cytogenetic abnormalities in acute leukemia complicating melphalan-treated multiple myeloma.Cancer Genet Cytogenet.1990,48:67-73.
5 Nilsson T,Nilsson L,Lenhoff S,et al.MDS/AML-associated cytogenetic abnormalities in multiple myeloma and monoclonal gammopathy of undetermined significance:evidence for frequent de novo occurr.ence and multipotent stem cell involvement of del(20q).Genes Chromosomes Cancer,2004,41:223-231.
6 肖志坚.骨髓增生异常综合征的诊断和治疗认识现状.国际输血及血液学杂志,2007,30:1-4.
2 Schwab M, Eichelbaum M, Fromm MF. Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol,2003,43:285-307.
3 Hoffmeyer S, Burk O, von Richter 0, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with Pglycoprotein expression and activity in vivo. Proc Natl Acad Sci USA, 2000, 97(7):3473-3478.
4 von Ahsen N, Richter M, Grupp C, et al. No influence of the MDR-1 C3435T polymorphism or a CYP3A4 promoter polymorphism (CYP3A4-V allele) on dose-adjusted cyclosporine A trough concentrations or rejection incidence in stable renal transplant recipients. Clin Chem, 2001, 47(6): 1048-1052.
5 Chowbay B, Cumaraswany S, Cheung YB, et al. Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Pharmacogenetics, 2003, 13(2): 89-95.
6 Yates CR, Zhang W, Song P, et al. The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients. J Clin Pharmacol, 2003, 43(6): 555-564.
7 Kuzuya T, Kobayashi T, Moriyama N, et al. Amlodipine, but not MDRl polymorphisms, alters the pharmacokinetics of cyclosporine A in Japanese kidney transplant recipients. Transplantation, 2003, 76(5):865-868.
8 Anglicheau D, Thervet E, Etienne I, et al. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther, 2004, 75(5): 422-433.
9 Zheng H, Schuetz E, Zeevi A, et al. Sequential analysis of tacrolimus dosing in adult lung transplant patients with ABCB1 haplotypes. J Clin Pharmacol, 2005, 45(4): 404-410.
10 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): 100-108.
11 Xie HG, Wood AJ, Kim RB, et al. Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics, 2004, 5(3): 243-272.
12 Hu YF, Qiu W, Liu ZQ, et al. Effects of genetic polymorphisms of CYP 3A4, CYP3A5 and MDR1 on cyclosporine pharmacokingetics after renal transplantation. Clin Exp Pharmacol Physiol, 2006, 33(11):1093-1098.
13 Min DI,Ellingrod VL,Marsh S.CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects.Ther Drug Monit,2004,26(5):524-528.
14 Haufroid V,Mourad M,Van Kerckhove V,et al.The effect of CYP3A5 and MDR1(ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients.Pharmacogenetics,2004,14(3):147-154.
15 杨崇礼,邵宗鸿.再生障碍性贫血//张之南,沈悌,编著.血液病诊断及疗效标准.第三版.北京:科学出版社.2007:19-23.
16 Wasilewska A,Zalewski G,Chyczewski L,et al.MDR-1 gene polymorphisms and clinical course of steroid-responsive nephrotic syndrome in children.Pediatr Nephrol,2007,22(1):44-51.
17 van Schaik RH,van der Heiden IP,van den Anker JN,et al.CYP3A5variant allele frequencies in Dutch Caucasians.Clin Chem,2002,48(10):1668-1671.
18 岑宇翔,陆志诚,汪华侨.汉族人MDR1 C3435T基因的多态性.解剖学研究,2004,26(1):11-13.
19 Kuehl R Zhang J,Lin Y,et al.Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.Nat Genet,2001,27(4):383-391.
20 Fredericks S,Jorga A,MacPhee IA,et al.Multi-drug resistance gene-1(MDR-1) haplotypes and the CYP3A5*1 genotype have no influence on ciclosporin dose requirements as assessed by CO or C2 measurements. Clin Transplant, 2007, 21(2): 252-257.
21 Bonhomme-Faivre L, Devocelle A, Saliba F, et al. MDR-1 C3435T polymorphism influences cyclosporine a dose requirement in liver-transplant recipients.Transplantation, 2004, 78(1):21-25.
22 Foote CJ, Greer W, Kiberd B, et al. Polymorphisms of multidrug resistance gene (MDR1) and cyclosporine absorption in de novo renal transplant patients. Transplantation, 2007, 83 (10): 1380-1384.
23 Foote CJ, Greer W, Kiberd BA, et al. MDR1 C3435T polymorphisms correlate with cyclosporine levels in de novo renal recipients.Transplant Proc, 2006, 38(9): 2847-2849.
24 Tanabe M, Ieiri I, Nagata N, et al. Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-l gene.J Pharmacol Exp Ther, 2001, 297(3):1137-1143.
25 Kioka N, Tsubota J, Kakehi Y, et al. P-glycoprotein gene (MDR1) cDNA from human adrenal: normal Pglycoprotein carries Gly185 with an altered pattern of multidrug resistance. BiochemBiophys Res Commun, 1989, 162(1): 224-231.
26 Song P, Lamba JK, Zhang L, et al. G2677T and C3435T genotype and haplotype are associated with hepatic ABCB1 (MDR1) expression. J Clin Pharmacol, 2006, 46(3): 373-379. Kumagai N,Benedict SH,Mills GB,et al.Cyclosporin A inhibits initiation but not progression of human T cell proliferation triggered by phorbol esters and calcium ionophores.J Immunol,1988,141(11):3747-3752.
2 张万起,元云峰,宓怀风.亲免素结合类免疫抑制剂作用的分子机理.中国药理学与毒理学杂志,2002,16(2):155-160.
3 Su B,Jacinto E,Hibi M,et al.JNK is involved in signal integration during costimulation of T lymphocytes.Cell,1994,77(5):727-736.
4 Matsuda S,Moriguchi T,Koyasu S,et al.T lymphocyte activation signals for interleuk in production involve activation of MKK6-p38and MKK7-SAPK/JNK signaling pathways sensitive to cyclosporin A.J Biol Chem,1998,273(20):12378-12382.
5 Karin M.The regulation of AP-1 activity by mitogen activated protein kinases.J Biol Chem,1995,270(28):16483-16486.
6 Karin M,De|hase M.JNK or IKK,AP-1 or NF-kappaB,which are the targets for MEK kinase 1 action? ProcNatl Acad Sci USA,1998,95(16):9067-9069.
7 Aoyama T,Yamano S,Waxman DJ,et al.Cytochrome P-450 hPCN3,a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver,cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. J Biol Chem, 1989, 264( 18): 10388-10395.
8 Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter, Annu Rev Biochem, 1993, 62:385-427.
9 Fricker G, Drewe J, Huwyler J, et al. Relevance of p-glycoprotein for the enteral absorption of cyclosporin A: In vitro in vivo correlation. Br J Pharmacol, 1996, 118(7): 1841-1847.
10 Burton PS, Conaradi RA, Hilgers AR,et al. Evidence for a polarized efflux for peptides in the apical membrane of Caco-2 cells. Biochem Biophys Res Commun, 1993, 190(3):760-766.
11 Stieger B, Fattinger K, Madon J, et al. Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology, 2000, 118(2): 422-430.
12 Song P, Lamba JK, Zhang L, et al. G2677T and C3435T genotype and haplotype are associated with hepatic ABCB1 (MDR1) expression. J Clin Pharmacol, 2006, 46(3):373-379.
13 Nakamura T, Sakaeda T, Horinouchi M, et al. Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin Pharmacol Ther, 2002, 71(4): 297-303.
14 Hitzl M, Schaeffeler E, Hocher B,et al. Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1).Pharmacogenetics, 2004, 14(5): 309-318.
15 Kimchi-Sarfaty C, Oh JM, Kim IW, et al. A "silent" polymorphism in the MDRl gene changes substrate specificity. Science, 2007,315(5811):525-528.
16 Foote CJ, Greer W, Kiberd Bet, et al. Polymorphisms of multidrug resistance gene (MDR1) and cyclosporine absorption in de novo renal transplant patients. Transplantation, 2007 , 83(10): 1380-1384.
17 Foote CJ, Greer W, Kiberd BA, et al. MDR1 C3435T polymorphisms correlate with cyclosporine levels in de novo renal recipients.Transplant Proc, 2006, 38(9):2847-2849.
18 Anglicheau D, Thervet E, Etienne I, et al. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther, 2004, 75(5): 422-433.
19 Haufroid V, Mourad M, Van Kerckhove V, et al. The effect of CYP3A5 and MDRl (ABCBl) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics. 2004, 14(3): 145-146.
20 Mai I, Stormer E, Goldammer M, et al. MDRl haplotypes do not affect the steady-state pharmacokinetics of cyclosporine in renal transplant patients. J Clin Pharmacol, 2003, 43(10):1101-1107.
21 Bonhomme-Faivre L,Devocelle A,Saliba F,et al.MDR-1 C3435T polymorphism influences cyclosporine a dose requirement in liver-transplant recipients.Transplantation.2004,78(1):21-25.
22 Chowbay B,Cumaraswamy S,Cheung YB,et al.Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporine disposition in heart transplant recipients.Pharmacogenetics,2003,13(2):89-95.
23 张亚同,杨莉萍,邵宏,等.MDR1基因C3435T多态性对重症肌无力患者环孢素血药浓度的影响.中国临床药理学与治疗学,2005,10(2);133-136
24 Daniel F,Loriot MA,Seksik P,et al.Multidrug resistance gene-1polymorphisms and resistance to cyclosporine A in patients with steroid resistant ulcerative colitis.Inflamm Bowel Dis,2007,13(1):19-23.
25 Hu YF,Qiu W,Liu ZQ,etal.Effects of genetic polymorphisms of CYP 3A4,CYP3A5 and MDR1 on cyclosporine pharmacokingetics after renal transplantation.Clin Exp Pharmacol Physiol,2006,33(11):1093-1098.
26 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.
27 Xie HG,Wood A J,Kim RB,et al.Genetic variability in CYP3A5 and its possible consequences.Pharmacogenomics,2004,5(3):243 -272.
28 Kuehl P,Zhang J,Lin Y,et al.Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.Nat Genet,2001,27(4):383-391.
29 Langaee TY,Gong Y,Yarandi HN,et al.Association of CYP3A5polymorphisms with hypertension and antihypertensive response to verapamil.Clin Pharmacol Ther,2007,81(3):386-391.
30 Min DI,Ellingrod VL,Marsh S.CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects.Ther Drug Monit,2004,26(5):524-528.
31 Haufroid V,Mourad M,Van Kerckhove V,et al.The effect of CYP3A5 and MDR1(ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients.Pharmacogenetics,2004,14(3):147-154.
32 Wadhwa NK,Schroeder TJ,O'Flaherty E,et al.The effect of oral metoclopramide on the absorption of cyclosporine.Transplant Proc,1987,19(1 Pt 2):1730-1733.
33 孙成春,郝俊文,李香铁,等.影响环孢素A血药浓度的因素分析.现代应用药学,1995,12(2):37-38.34 Hughes CM,Swanton JG,Collier PS.The effect of three H2 receptor antagonists on the disposition of cyclosporin A in the in situ perfused rat liver model.Biopharm Drug DislSos,1995,16(9):719-733.
35 Reichenspurner H,Meiser BM,Muschiol F,et al.The influence of gastrointestinal agents on resorption and metabolism of cyclosporine after heart transplantation:experimental and clinical results.J Heart Lung Transplant,1993,12(6 Pt 1):987-992.
36 朱金照,冷恩红,陈东风.红霉素促胃动力作用的研究及临床应用.河北医科大学学报,2000,21(1):60-62
37 王开贞,徐红.红霉素的胃肠反应机制与防治研究.中国临床医生,2003,31(3):49-60.
38 Ohba M,Ohnishi N,Komada F,et al.Effect of clarithromycin on the bioavailability of cyclosporin in rats.Biol Pharm Bull,1996,19(5):733-737.
39 Sketris IS,.Wright MR,West ML.Possible role of the intestinal P-450enzyme system in a cyclosporine-clarithromycin interaction.Pharmacotherapy,1996,16(2):301-305.
40 Capone D,Aiello C,Santoro GA,et al.Drug interaction between cyclosporine and two antimicrobial agents,josamycin and rifampicin,in organ-transplanted patients.Int J Clin Pharmacol Res,1996,16(2-3):73-76.
41 McLellan.RA,Drobitch RK,Monshouwer M,et al.Fluoroquinolone antibiotics inhibit cytochrome P450-mediated microsomal drug metabolism in rat and human.Drug Metab Dispos,1996,24(10):1134-1138.
42 McLellan RA,Drobitch RK,McLellan H,et al.Norfloxacin interferes with cyclosporine disposition in pediatric patients undergoing renal transplantation.Clin Pharmacol Ther,1995,58(3):322-327.
43 Hoey LL,Lake KD.Does ciprofloxacin interact with cyclosporine?Ann Pharmacother,1994,28(1):93-96.
44 Kr(u|¨)ger HU,Schuler U,Proksch B,et al.Investigation of potential interaction of ciprofloxacin with cyclosporine in bone marrow transplant recipients.Antimicrob Agents Chemother,1990,34(6):1048-1052.
45 Campana C,Regazzi MB,Buggia I,et al.Clinically significant drug interactions with cyclosporin.An update.Clin Pharmacokinet,1996,30(2):141-179.
46 Kwan JT,Foxall PJ,Davidson DG,et al.Interaction of cyclosporin and itraconazole.Lancet,1987,2(8553):282.
47 Canafax DM,Graves NM,Hilligoss DM,et al.Increased cyclosporine levels as a result of simultaneous fluconazole and cyclosporine therapy in renal transplant recipients:a double-blind,randomized pharmacokinetic and safety study.Transplant Proc,1991,23(1 Pt 2):1041-1042.
48 闫正华,王茂义,黄猛,等.肾移植患者应用更昔洛韦后环孢菌素的药动学及生化指标的研究.西安医科大学学报,1999,20(2):42-44.
49 Hannemann J, Wunderle W, Yousif T, et al. Toxic effect of concomitant administration of cyclosporin A and acyclovir on renal function and morphology in rats. Arch Toxicol, 1997, 71(9):556-562.
50 Grino JM, Sabate I, Castelao AM, et al. Influence of diltiazem on cyclosporin clearance. Lancet, 1986, 1(8494): 1387.
51 Shennib H, Auger JL. Diltiazem improves cyclosporine dosage in cystic fibrosis lung transplant recipients . J Heart Lung Transplant,1994, 13 (2) :292-296.
52 Duvoux C, Cherqui D, Di Martino V, et al. Nicardipine as antihypertensive therapy in liver transplant recipients: results of long-term use. Hepatology, 1997, 25(2):430-433.
53 Martin JE, Daoud AJ, Schroeder TJ, et al. The clinical and economic potential of cyclosporin drug interactions. Pharmacoeconomics, 1999,15(4):317-337.
54 Islam SI, Masuda QN, Bolaji 00, et al. Possible interaction between cyclosporine and glibenclamide in posttransplant diabetic patient.Ther Drug Monit, 1996 ,18 (5) :624-626.
55 Chidester PD, Connito DJ. Interaction between glipizide and cyclosporine: report of two cases. Transplant Proc, 1993,25(2):2136-2137.
56 Carstensen H, Jacobsen N, Dieperink H. Interaction between cyclosporin A and phenobarbitone. Br J Clin Pharmacol, 1986, 21: 550-551
57 Klintmalm G,S(a|¨)we J,Ringden O,et al.Cyclosporine plasma levels in renal transplant patients.Association with renal toxicity and allograft rejection.Transplantation,1985,39(2):132-137.
58 余爱荣,吴笑春,李罄,等.联苯双酯对肾移植受者CsA全血浓度的影响及肝毒性的防护作用.中国临床药理学与治疗学杂志,2004,9(5):548-550.
59 吴家清,刘东,唐斌,等.联苯双酯对肾移植患者CsA血药浓度的影响.广东医学,2004,25(1):85-86.
60 Kaplan B,Friedman G,Jacobs M,et al.Potential interaction of troglitazone and cyclosporine.Transplantation,1998,27;65(10):1399-1400.
61 Boissonnat P,de Lorgeril M,Perroux V,et al.A drug interaction study between ticlopodine and cyclosporin in heart transplant recipients.Eur J Clin Pharmacol,1997,53(1):39-45.
1 Amiel A,Yukla M,Yogev S,et al.Deletion of 5q31 and 7q31 in patients with stable melphalan-treated multiple myeloma.Cancer Genet Cytogenet,2004,152:84-87.
2 Ishiia Y,Hsiaoa HH,Sashidaa G,et al.Derivative(1;7)(q10;p10) in multiple myeloma.A sign of therapy-related hidden myelodysplastic syndrome.Cancer Genetics and Cytogenetics,2006,167:131-137.
3 Mauritzson N,Albin M,Rylander L,et al.Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976-1993 and on 5098unselected cases reported in the literature 1974-2001.Leukemia,2002,16:2366-23.78.
4 Rodjer S,Swolin B,Weinfeld A,et al.Cytogenetic abnormalities in acute leukemia complicating melphalan-treated multiple myeloma.Cancer Genet Cytogenet.1990,48:67-73.
5 Nilsson T,Nilsson L,Lenhoff S,et al.MDS/AML-associated cytogenetic abnormalities in multiple myeloma and monoclonal gammopathy of undetermined significance:evidence for frequent de novo occurr.ence and multipotent stem cell involvement of del(20q).Genes Chromosomes Cancer,2004,41:223-231.
6 肖志坚.骨髓增生异常综合征的诊断和治疗认识现状.国际输血及血液学杂志,2007,30:1-4.