Hempfling Wolfgang, Grunhage Frank, Dilger Karin, Reichel Christoph, Beuers Ulrich, Sauerbruch Tilman
Department of Medicine II, Klinikum Grosshadern, University of Munich, Munich, Germany.
Hepatology. 2003 Jul;38(1):196-202. doi: 10.1053/jhep.2003.50266.
Budesonide has been discussed as a potential treatment option in primary biliary cirrhosis (PBC). Therefore, we studied the pharmacokinetics and pharmacodynamics of budesonide in patients with PBC stage I/II and stage IV. Twelve patients with early PBC stage I/II and 7 patients with PBC stage IV under continuous treatment with ursodeoxycholic acid (UDCA) were enrolled in an exploratory trial. Each patient received oral budesonide for 3 weeks at weekly increasing dosages of 3 mg once to thrice per day. Budesonide and cortisol plasma levels, urinary cortisol excretion, serum liver tests, and immunoglobulins were determined on days 1, 7, and 21 of the study. Patients with PBC stage IV showed significantly higher peak plasma concentrations (4.9 +/- 3.5 vs. 1.5 +/- 0.4 ng/mL; P <.05) and areas under the plasma concentration-time curves (AUC) (23.2 +/- 16.8 vs. 5.1 +/- 1.4 hours. ng/mL, P <.01, total AUC extrapolated to infinity [AUC(0- infinity )]) after a single dose of 3 mg budesonide when compared with patients with PBC stage I/II. Equally, AUC of budesonide were significantly increased under a multiple dose regimen on day 21 (14.0 +/- 11.6 vs. 5.0 +/- 1.9 hours. ng/mL, P <.01, AUC at steady state from dosing time to 8 hours [AUC(ss,0-8 h)]). Higher levels of budesonide were related to a significant decrease in plasma cortisol and reduction of urinary cortisol excretion in patients with stage IV disease. Two patients with stage IV disease developed portal vein thrombosis (PVT). In conclusion, administration of budesonide leads to markedly elevated plasma levels in cirrhotic patients with PBC associated with serious adverse drug reactions. Thus, further evaluation of combined treatment with UDCA may be considered in early-stage PBC but not in cirrhotic patients with PBC.
布地奈德已被探讨作为原发性胆汁性肝硬化（PBC）的一种潜在治疗选择。因此，我们研究了布地奈德在I/II期和IV期PBC患者中的药代动力学和药效学。12例I/II期早期PBC患者和7例接受熊去氧胆酸（UDCA）持续治疗的IV期PBC患者参加了一项探索性试验。每位患者口服布地奈德3周，每周剂量递增，每天1次至3次，每次3mg。在研究的第1天、第7天和第21天测定布地奈德和皮质醇血浆水平、尿皮质醇排泄、血清肝功能检查和免疫球蛋白。与I/II期PBC患者相比，IV期PBC患者在单次服用3mg布地奈德后，血浆峰值浓度（4.9±3.5对1.5±0.4ng/mL；P<0.05）和血浆浓度-时间曲线下面积（AUC）（23.2±16.8对5.1±1.4小时·ng/mL，P<0.01，外推至无穷大的总AUC[AUC(0-∞)]）显著更高。同样，在第21天的多剂量方案下，布地奈德的AUC显著增加（14.0±11.6对5.0±1.9小时·ng/mL，P<0.01，给药时间至8小时的稳态AUC[AUC(ss,0-8h)]）。较高水平的布地奈德与IV期疾病患者血浆皮质醇显著降低和尿皮质醇排泄减少有关。2例IV期疾病患者发生门静脉血栓形成（PVT）。总之，布地奈德给药导致PBC肝硬化患者血浆水平显著升高，并伴有严重的药物不良反应。因此，对于早期PBC患者可考虑进一步评估UDCA联合治疗，但对于PBC肝硬化患者则不适用。
