中国临床药学杂志
中國臨床藥學雜誌
중국림상약학잡지
CHINESE JOURNAL OF CLINICAL PHARMACY
2008年
3期
141-147
,共7页
邱晓燕%焦正%仲珑瑾%张明%马春来%张亮%钟明康
邱曉燕%焦正%仲瓏瑾%張明%馬春來%張亮%鐘明康
구효연%초정%중롱근%장명%마춘래%장량%종명강
环孢素%多药耐药基因%P-糖蛋白%单核苷酸多态性%肾移植
環孢素%多藥耐藥基因%P-糖蛋白%單覈苷痠多態性%腎移植
배포소%다약내약기인%P-당단백%단핵감산다태성%신이식
ciclosporin%multidrug resistant gene 1%P-glycoprotein%single nucleotide polymorphisms%renal transplantation
目的 探讨中国汉族人中肾移植患者的多药耐药基因(MDR1)外显子exon12 C1236T、exon21 G2677T/A、exon26 C3435T的单核苷酸多态性对免疫抑制剂环孢素(CsA)药动学的影响.方法 采用聚合酶联反应和限制性内切片段长度多态性(PCR-RFLP)的方法对89例肾移植术后的患者进行MDR1基因分型.单克隆抗体荧光免疫偏振法测定患者术后CsA的谷浓度(c0)及服药后2h浓度(c2).比较不同基因型之间CsA浓度剂量比值的差异.结果 在89例肾移植患者中,等位基因1236T、2677T、2677A、3435T突变频率分别为66%、43%、18%和37%.肾移植术后1mo内,G2677T/A基因多态性与CsA的药动学有相关性,2个等位基因都发生突变的患者,其剂量校正c0,在术后1～7d、8～15d和16～30d比野生型分别提高51%(P=0.005)、32%(P=0.002)和63%(P<0.001).在术后16～30d,无论携带有1个或2个突变等位基因的患者,剂量校正c2都要比野生型患者高26%(P=0.007)和19%(P=0.041).C1236T的剂量校正c0在术后8～15d和16～30d各基因型之间差异显著,但以CC型与CT型差异最为显著,而CC型与TT型在16～30d,则差异无统计学意义(P>0.05).C3435T的不同基因型之间,剂量校正c0、c2差异无统计学意义(P>0.05).结论 在中国汉族肾移植患者中,MDR1的exon12 C1236T和exon21 G2677/A的单核苷酸多态性与移植术后1mo内CsA的药动学有相关性.但把这种相关性应用在在临床上,对MDR1进行遗传学检测,以优化CsA的剂量,尚待进一步的研究.
目的 探討中國漢族人中腎移植患者的多藥耐藥基因(MDR1)外顯子exon12 C1236T、exon21 G2677T/A、exon26 C3435T的單覈苷痠多態性對免疫抑製劑環孢素(CsA)藥動學的影響.方法 採用聚閤酶聯反應和限製性內切片段長度多態性(PCR-RFLP)的方法對89例腎移植術後的患者進行MDR1基因分型.單剋隆抗體熒光免疫偏振法測定患者術後CsA的穀濃度(c0)及服藥後2h濃度(c2).比較不同基因型之間CsA濃度劑量比值的差異.結果 在89例腎移植患者中,等位基因1236T、2677T、2677A、3435T突變頻率分彆為66%、43%、18%和37%.腎移植術後1mo內,G2677T/A基因多態性與CsA的藥動學有相關性,2箇等位基因都髮生突變的患者,其劑量校正c0,在術後1～7d、8～15d和16～30d比野生型分彆提高51%(P=0.005)、32%(P=0.002)和63%(P<0.001).在術後16～30d,無論攜帶有1箇或2箇突變等位基因的患者,劑量校正c2都要比野生型患者高26%(P=0.007)和19%(P=0.041).C1236T的劑量校正c0在術後8～15d和16～30d各基因型之間差異顯著,但以CC型與CT型差異最為顯著,而CC型與TT型在16～30d,則差異無統計學意義(P>0.05).C3435T的不同基因型之間,劑量校正c0、c2差異無統計學意義(P>0.05).結論 在中國漢族腎移植患者中,MDR1的exon12 C1236T和exon21 G2677/A的單覈苷痠多態性與移植術後1mo內CsA的藥動學有相關性.但把這種相關性應用在在臨床上,對MDR1進行遺傳學檢測,以優化CsA的劑量,尚待進一步的研究.
목적 탐토중국한족인중신이식환자적다약내약기인(MDR1)외현자exon12 C1236T、exon21 G2677T/A、exon26 C3435T적단핵감산다태성대면역억제제배포소(CsA)약동학적영향.방법 채용취합매련반응화한제성내절편단장도다태성(PCR-RFLP)적방법대89례신이식술후적환자진행MDR1기인분형.단극륭항체형광면역편진법측정환자술후CsA적곡농도(c0)급복약후2h농도(c2).비교불동기인형지간CsA농도제량비치적차이.결과 재89례신이식환자중,등위기인1236T、2677T、2677A、3435T돌변빈솔분별위66%、43%、18%화37%.신이식술후1mo내,G2677T/A기인다태성여CsA적약동학유상관성,2개등위기인도발생돌변적환자,기제량교정c0,재술후1～7d、8～15d화16～30d비야생형분별제고51%(P=0.005)、32%(P=0.002)화63%(P<0.001).재술후16～30d,무론휴대유1개혹2개돌변등위기인적환자,제량교정c2도요비야생형환자고26%(P=0.007)화19%(P=0.041).C1236T적제량교정c0재술후8～15d화16～30d각기인형지간차이현저,단이CC형여CT형차이최위현저,이CC형여TT형재16～30d,칙차이무통계학의의(P>0.05).C3435T적불동기인형지간,제량교정c0、c2차이무통계학의의(P>0.05).결론 재중국한족신이식환자중,MDR1적exon12 C1236T화exon21 G2677/A적단핵감산다태성여이식술후1mo내CsA적약동학유상관성.단파저충상관성응용재재림상상,대MDR1진행유전학검측,이우화CsA적제량,상대진일보적연구.
AIM To evaluate retrospectively the effects of genetic polymorphisms in exon 12 C1236T, exon 21 G2677T/A and exon 26 C3435T of MDR1 gene on ciclosporin (CsA) pharmacokinetics in Chinese adult renal transplant patients within the first month post-operation. METHODS Eight-nine renal transplant recipients receiving CsA were genotyped by the assay of polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) for the MDR1. The concentrations of CsA before (trough concentration, c0) and 2h (peak concentration, c2) after administration were determined by fluorescence polarization immunoassay. The dose per weight adjusted CsA concentrations were correlated with corresponding genotype. RESULTS The frequency of 1236T allele, 2677T allele, 2677A allele and 3435T allele in current study cohort were 66%, 43%, 18% and 37%, respectively. A correlation was found between the dose-adjusted CsA concentrations and polymorphisms in exon 21. Dose-adjusted c0 was higher in patients carrying two mutant alleles than those with homozygous wild-type genotype, as follows: 51% in 1 to 7d (P=0.005) υs 32% during 8 to 15d (P=0.002) υs 63% (P<0.001) during 16 to 30d. Dose-adjusted c2 was also higher in patients carrying one or two mutant alleles than those with homozygous wild-type genotype, as follows: 26% (P=0.007) υs 19% (P=0.041). Regarding to exon 12, patients with CT and TT genotype had 30% (P=0.002) and 18% (P=0.025) lower dose-adjusted c0 compared to patients with CC genotype during 8 to 15d post-transplantation, respectively, while only patients with CT genotype had lower dose-adjusted c0 (36%, P=0.002) during 16 to 30d. In addition, no evidence was found supporting a role for the C3435T polymorphism in CsA pharmacokinetics. CONCLUSION Our study in Chinese Han renal transplant patients demonstrate that a correlation existed between MDR1 exon 12 C1236T and exon 21 G2677T/A SNP and CsA pharmacokinetics in the early stage after transplantation.
