Macphee Iain A M, Fredericks Salim, Tai Tracy, Syrris Petros, Carter Nicholas D, Johnston Atholl, Goldberg Lawrence, Holt David W
Division of Renal Medicine St. George's Hospital Medical School, London, United Kingdom.
Transplantation. 2002 Dec 15;74(11):1486-9. doi: 10.1097/00007890-200212150-00002.
There is marked heterogeneity in blood concentrations of tacrolimus following standard body-weight-based dosing. This is most apparent in black patients, who have a higher dose requirement when compared with other ethnic groups. Differences in intestinal P-glycoprotein and hepatic and intestinal cytochrome P4503A activity have been postulated as contributing to this problem.
The dose-normalized blood concentrations of tacrolimus at 3 months after renal transplantation were related to CYP3AP1 and multiple drug resistance (MDR)-1 genotypes determined by polymerase chain reaction followed by restriction fragment length polymorphism analysis.
We found that a single nucleotide polymorphism in the CYP3AP1 pseudogene (A/G(44)) that previously has been noted to be more common in African Americans and strongly associated with hepatic CYP3A5 activity correlated well with the tacrolimus dose requirement. A weaker association was found for a polymorphism in the MDR-1 gene, which influences intestinal P-glycoprotein expression.
The CYP3AP1 genotype is a major factor in determining the dose requirement for tacrolimus, and genotyping may be of value in planning patient-specific drug dosing.
在基于标准体重给药后，他克莫司的血药浓度存在显著异质性。这在黑人患者中最为明显，与其他种族群体相比，他们需要更高的剂量。肠道P-糖蛋白以及肝脏和肠道细胞色素P4503A活性的差异被认为是导致这一问题的原因。
肾移植后3个月时他克莫司的剂量标准化血药浓度与通过聚合酶链反应继以限制性片段长度多态性分析确定的CYP3AP1和多药耐药（MDR）-1基因型相关。
我们发现，CYP3AP1假基因中的一个单核苷酸多态性（A/G(44)），此前已注意到在非裔美国人中更为常见且与肝脏CYP3A5活性密切相关，与他克莫司的剂量需求密切相关。对于影响肠道P-糖蛋白表达的MDR-1基因中的一个多态性，发现其关联性较弱。
CYP3AP1基因型是决定他克莫司剂量需求的主要因素，基因分型在规划个体化给药方案中可能具有价值。
