耐多药resistance-associated蛋白2 (MRP2 / ABCC2)单明显影响他克莫司在肾移植受者的药物动力学。

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小笠原K Chitnis SD Gohh,基督徒U, Akhlaghi F

耐多药resistance-associated蛋白2 (MRP2 / ABCC2)单明显影响他克莫司在肾移植受者的药物动力学。

Pharmacokinet。2013年9月,52 (9):751 - 62。doi: 10.1007 / s40262 - 013 - 0069 - 2。

PubMed ID

23633119 (在PubMed

]

文摘

背景和目的:他克莫司是一种免疫抑制药物用于预防肾移植受者的同种异体移植物排斥反应。将会呈现出一种狭窄的治疗指数和大药代动力学变化。他克莫司主要代谢细胞色素P450 (CYP) 3 a4和a5和射流通过磷酸腺苷磁带(ABC)转运蛋白22 (P-gp)等种代号为ABCB1的编码的基因。CYP3A5 * 3的药物动力学的影响他克莫司已经研究的很透彻了。另一方面,在其他基因多态性的贡献是有争议的。此外,其他射流转运蛋白的参与比他克莫司P-gp性格是不确定的。本研究旨在调查CYP3As的遗传多态性和射流的影响他克莫司的药物转运蛋白。对象和方法:总共有500从102年成人的他克莫司血药浓度的稳定的肾移植受者是包括在分析中。基因多态性在CYP3A4和CYP3A5基因测定。此外,射流转运蛋白的基因,包括P-gp种代号为ABCB1的(),耐多药resistance-associated蛋白质(MRP2 / ABCC2)和乳腺癌耐药蛋白(BCRP / ABCG2)基因分型。 For ABCC2 gene, haplotypes were determined as follows: H1 (wild type), H2 (1249G>A), H9 (3972C>T) and H12 (-24C>T and 3972C>T). Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling. RESULTS: Analyses revealed that the CYP3A5 expressers (CYP3A5*1 carriers) and MRP2 high-activity group (ABCC2 H2/H2 and H1/H2) showed a decreased dose-normalized trough concentration of tacrolimus by 2.3-fold (p < 0.001) and 1.5-fold (p = 0.007), respectively. The pharmacokinetics of tacrolimus were best described using a two-compartment model with first order absorption and an absorption lag time. In the population pharmacokinetic analysis, CYP3A5 expressers and MRP2 high-activity groups were identified as the significant covariates for tacrolimus apparent clearance expressed as 20.7 x (age/50)(-0.78) x 2.03 (CYP3A5 expressers) x 1.40 (MRP2 high-activity group). No other CYP3A4, ABCB1 or ABCG2 polymorphisms were associated with the apparent clearance of tacrolimus. CONCLUSIONS: This is the first report showing that MRP2/ABCC2 has a crucial impact on the pharmacokinetics of tacrolimus in a haplotype-specific manner. Determination of the ABCC2 as well as CYP3A5 genotype may be useful for more accurate tacrolimus dosage adjustment.

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药物转运蛋白

药物	转运体	类	生物	药理作用	行动
红霉素	微管的multispecific有机阴离子转运体1	蛋白质	人类	未知的	底物	细节