Masuda Satohiro, Goto Maki, Kiuchi Tetsuya, Uemoto Shinji, Kodawara Takaaki, Saito Hideyuki, Tanaka Koichi, Inui Ken-ichi
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Liver Transpl. 2003 Oct;9(10):1108-13. doi: 10.1053/jlts.2003.50179.
We evaluated levels of intestinal expression of absorptive-barrier P-glycoprotein (PGP) and cytochrome P-450 IIIA4 (CYP3A4) and immunosuppressant therapy in a patient who underwent living donor liver transplantation (LDLT) and received a second living donor liver transplant after chronic rejection of the first. PGP and CYP3A4 expression were measured using part of a Roux-en-Y limb. After the first LDLT, the concentration-dose ratio of orally administered tacrolimus was 159.8 +/- 125.3 (average +/- SD of 32 different days), similar to the average for 46 recipients of living donor liver transplants in our hospital (161.3 +/- 88.1). However, the recipient required very large oral doses of cyclosporine (703.9 +/- 385.4 mg/d, average +/- SD of 13 different days) after the second LDLT. Although intestinal PGP level was increased markedly at the second LDLT, CYP3A4 level was decreased. In addition, levels of messenger RNA expression of several gene products related to the local inflammation, such as cyclooxygenase 2, interleukin-1beta (IL-1beta), IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha, were increased. These results suggest that hepatic failure after LDLT, including chronic rejection and/or cholangitis, was accompanied by upregulation of intestinal PGP expression, which could depress the bioavailability of the immunosuppressant.
我们评估了一名接受活体肝移植（LDLT）的患者在首次移植慢性排斥后接受第二次活体肝移植时，其肠道中吸收屏障P-糖蛋白（PGP）和细胞色素P-450 IIIA4（CYP3A4）的表达水平以及免疫抑制治疗情况。使用Roux-en-Y肠袢的一部分来测量PGP和CYP3A4的表达。首次LDLT后，口服他克莫司的浓度-剂量比为159.8±125.3（32个不同日子的平均值±标准差），与我院46名活体肝移植受者的平均值（161.3±88.1）相似。然而，第二次LDLT后，该受者需要非常大剂量的口服环孢素（703.9±385.4mg/d，13个不同日子的平均值±标准差）。虽然第二次LDLT时肠道PGP水平显著升高，但CYP3A4水平却下降了。此外，与局部炎症相关的几种基因产物的信使核糖核酸表达水平，如环氧合酶2、白细胞介素-1β（IL-1β）、IL-2、IL-6、IL-8、IL-10和肿瘤坏死因子-α，均有所增加。这些结果表明，LDLT后的肝衰竭，包括慢性排斥和/或胆管炎，伴有肠道PGP表达上调，这可能会降低免疫抑制剂的生物利用度。
