Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation
Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation
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DOI：
10.1046/j.1523-1755.2002.00531.x
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发表时间：
2002-09-01
影响因子：
19.6
通讯作者：
Remuzzi, G
中科院分区：
文献类型：
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作者：
Cattaneo, D;Perico, N;Remuzzi, G
背景资料。已有研究表明，类固醇可诱导肝脏葡萄糖醛酸基转移酶(GT)表达，增强代谢霉酚酸(MPA)的尿苷二磷酸-GT的活性。然而，类固醇对甲孕酮药代动力学的影响到目前为止还没有研究。作为节省类固醇的临床试验的一部分，我们研究了类固醇对26例肾移植受者甲孕酮生物利用度的影响。尽管MMF剂量随时间变化不明显，但标准化的MPAUC(0-12h)在术后1个月(三联疗法，高剂量激素)低于术后6个月(三联疗法，低维持剂量，32.94+/-10.98比50.87+/-22.37µg/mL)。H；P<；0.01)。在激素逐渐减少和停药期间(TX后6个月至21个月)，血浆MPA谷值、峰值浓度及AUC(0~12h)逐渐升高，而血浆MPA清除率及MPAG谷值下降。肾功能自始至终稳定。由于环孢素A(CsA)可能干扰甲孕酮的药代动力学，对12例肾移植术后21个月仍在接受三联治疗(MMF、CsA和类固醇)的患者进行了甲孕酮和环孢素A的测定。尽管CsA暴露相似，但在Tx治疗后21个月，对照组的MPAUC(0-12h)显著低于联合治疗组，MPAG谷值显著高于联合治疗组。这些发现表明，类固醇干扰了MPA的生物利用度，停药会导致更高的MPA暴露，这至少可以部分补偿剩余的CsA和MMF双重治疗所获得的较低的免疫抑制水平。
Background. Steroids have been shown to induce the hepatic glucuronyltransferase (GT) expression enhancing the activity of uridine diphosphate-GT, the enzyme responsible for mycophenolic acid (MPA) metabolism. The impact of steroids on MPA pharmacokinetics, however, has not been investigated to date.Methods. As a part of a steroid-sparing clinical trial, we studied the effect of steroids on MPA bioavailability in 26 kidney transplant recipients.Results. Despite that the MMF dose did not change significantly with time, dose-normalized MPA AUC(0-12h) was lower during the first month (triple therapy, high doses of steroids) than at month 6 post-surgery (triple therapy, low maintenance dose of steroids (32.94 +/- 10.98 vs. 50.87 +/- 22.37 mug/mL . h; P < 0.01). During the steroid tapering and withdrawal phase (from month 6 to 21 post-Tx), plasma MPA trough and peak concentration as well as AUC(0-12h) progressively increased, while plasma MPA clearance and MPAG (the major MPA metabolite) trough levels declined. Renal function was stable throughout. Since cyclosporine A (CsA) may interfere with MPA pharmacokinetics, MPA and CsA also were measured in an additional control group of 12 kidney transplant patients at month 21 post-Tx who were still on triple therapy (MMF, CsA and steroids). Despite a similar CsA exposure, the control group had a significantly lower MPA AUC(0-12h) and higher MPAG trough concentration than patients on dual therapy at month 21 post-Tx.Conclusion. These findings indicate that steroids interfere with MPA bioavailability, and that discontinuation of the drug results in higher MPA exposure, which may compensate at least in part for the lower immunosuppressive level achieved with the remaining dual therapy with CsA and MMF.