Tuteja S, Alloway R R, Johnson J A, Gaber A O
Department of Pharmacy, University of Kentucky, Lexington, USA.
Transplantation. 2001 May 15;71(9):1303-7. doi: 10.1097/00007890-200105150-00021.
Tacrolimus, a substrate of CYP3A, has low and variable bioavailability similar to cyclosporine. Co-administration of ketoconazole, potent inhibitor of gut and hepatic CYP3A, has been shown to increase tacrolimus bioavailability in healthy volunteers. The purpose of this study is to assess the role of gut metabolism in the overall bioavailability of tacrolimus in a renal transplant population.
We prospectively studied 19 adult renal transplant recipients who were receiving tacrolimus as part of a quadruple, sequential immunosuppression regimen. Each patient received tacrolimus (4-hr intravenous dose of 0.04 mg/kg between postoperative days 2 and 4). Whole blood samples were collected over 24 hr. After a 24-hr washout period, a single oral dose of ketoconazole (400 mg) was administered followed by the same intravenous dose of tacrolimus, and subsequent samples were obtained. Steady state oral pharmacokinetic profiles were obtained between 1 and 3 months after transplant while patients were receiving twice daily dosing of tacrolimus to maintain whole blood levels between 10 and 20 ng/ml. Two days later, 400 mg of ketoconazole was administered orally 2 hr before to the morning dose. Whole blood samples were collected over 12 hr.
In the absence of ketoconazole, 8.0% of the tacrolimus dose underwent first pass metabolism (E(H)), whereas in the presence of ketoconazole, first pass metabolism was 6.2% (P=0.01). Based on this difference in first pass metabolism, an increase of 2% in bioavailability is expected, but an increase of 47% is observed (P=0.001).
This indicates that the gut metabolism of tacrolimus is extensive and contributes significantly to its bioavailability.
他克莫司是细胞色素P450 3A（CYP3A）的底物，其生物利用度较低且变化不定，与环孢素类似。酮康唑是肠道和肝脏CYP3A的强效抑制剂，已证明在健康志愿者中，酮康唑与他克莫司合用可提高他克莫司的生物利用度。本研究的目的是评估肠道代谢在肾移植人群中他克莫司总体生物利用度中的作用。
我们前瞻性地研究了19例接受他克莫司治疗的成年肾移植受者，他克莫司是四联序贯免疫抑制方案的一部分。每位患者接受他克莫司（术后第2至4天静脉滴注4小时，剂量为0.04mg/kg）。在24小时内采集全血样本。经过24小时的洗脱期后，口服单剂量酮康唑（400mg），随后给予相同静脉剂量的他克莫司，并采集后续样本。在移植后1至3个月期间，当患者接受他克莫司每日两次给药以维持全血水平在10至20ng/ml时，获得稳态口服药代动力学曲线。两天后，在早晨给药前2小时口服400mg酮康唑。在12小时内采集全血样本。
在无酮康唑的情况下，他克莫司剂量的8.0%经历首过代谢（E(H)），而在有酮康唑的情况下，首过代谢为6.2%（P=0.01）。基于首过代谢的这种差异，预计生物利用度会增加2%，但观察到增加了47%（P=0.001）。
这表明他克莫司的肠道代谢广泛，对其生物利用度有显著贡献。
