Kuzuya Takafumi, Kobayashi Takaaki, Moriyama Natsuko, Nagasaka Takaharu, Yokoyama Itsuo, Uchida Kazuharu, Nakao Akimasa, Nabeshima Toshitaka
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Showa-ku, Nagoya, Japan.
Transplantation. 2003 Sep 15;76(5):865-8. doi: 10.1097/01.TP.0000084873.20157.67.
Cyclosporine A (CsA) is a critical immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Many factors, including P-glycoprotein (PGP), influence the oral bioavailability and interpatient variability of CsA. A number of polymorphisms have been identified in the human MDR1 gene, and some of them have been found to be associated with an altered expression of PGP. We have investigated the role of these polymorphisms in CsA absorption from kidney transplant recipients. In addition, we also investigated the effect of amlodipine on CsA absorption.
The area under the time-concentration curve from 0 to 2 hr (AUC(0-2)) estimated by the trapezoidal rule was used for the evaluation of extent of CsA absorption. The genotypes were identified by a polymerase chain reaction, restriction fragment length polymorphism analysis.
No association was found between polymorphisms in the MDR1 and CsA AUC(0-2)/dose/kg. In contrast, the combination of amlodipine significantly increased CsA AUC(0-2)/dose/kg (706.2 microg x hr/L to 819.2 microg x hr/L, P<0.05). Furthermore, we attempted to compare MDR1 polymorphisms and the absorption of CsA again without patients receiving amlodipine, but there was still no significant difference.
There is no relationship between polymorphisms for MDR1 and CsA absorption, suggesting polymorphisms for MDR1 cannot account for the interpatient variability of CsA. Amlodipine, which is the substrate of PGP, significantly increased CsA absorption. These results indicate that PGP plays a significant role in CsA absorption, but its polymorphisms could not influence the CsA absorption.
环孢素A（CsA）是一种关键的免疫抑制药物，治疗窗窄，药代动力学存在广泛的个体间差异。许多因素，包括P-糖蛋白（PGP），影响CsA的口服生物利用度和患者间变异性。人类多药耐药基因1（MDR1）中已鉴定出多种多态性，其中一些与PGP表达改变有关。我们研究了这些多态性在肾移植受者CsA吸收中的作用。此外，我们还研究了氨氯地平对CsA吸收的影响。
采用梯形法则估算0至2小时的时间-浓度曲线下面积（AUC(0-2)），以评估CsA的吸收程度。通过聚合酶链反应、限制性片段长度多态性分析鉴定基因型。
未发现MDR1多态性与CsA的AUC(0-2)/剂量/千克之间存在关联。相比之下，氨氯地平联合用药显著增加了CsA的AUC(0-2)/剂量/千克（从706.2微克·小时/升增至819.2微克·小时/升，P<0.05）。此外，我们试图在未接受氨氯地平治疗的患者中再次比较MDR1多态性与CsA的吸收情况，但仍无显著差异。
MDR1多态性与CsA吸收之间无关联，提示MDR1多态性不能解释CsA的患者间变异性。作为PGP底物的氨氯地平显著增加了CsA的吸收。这些结果表明，PGP在CsA吸收中起重要作用，但其多态性不会影响CsA的吸收。
