环孢素与西罗莫司对肾移植患者霉酚酸药代动力学影响的比较。
A comparison of the effect of ciclosporin and sirolimus on the pharmokinetics of mycophenolate in renal transplant patients.
作者信息
Picard Nicolas, Prémaud Aurélie, Rousseau Annick, Le Meur Yannick, Marquet Pierre
机构信息
Laboratory of Pharmacology, Faculty of Medicine, University of Limoges, France.
出版信息
Br J Clin Pharmacol. 2006 Oct;62(4):477-84. doi: 10.1111/j.1365-2125.2006.02509.x.
AIM
To compare the pharmacokinetics of mycophenolic acid when given with either ciclosporin or sirolimus, and investigate in vitro the potential effect of ciclosporin, sirolimus, tacrolimus and everolimus on mycophenolic acid metabolism.
METHODS
In renal transplant patients given mycophenolate mofetil in combination with ciclosporin (n = 19) or sirolimus (n = 12), concentration-time profiles of mycophenolic acid, mycophenolic-acid-phenyl-glucuronide, mycophenolic-acid-acyl-glucuronide and mycophenolic-acid-phenyl-glucoside were determined at one month post-transplant. The effect of immunosuppressive drugs on mycophenolic acid glucuronidation and glycosylation was investigated in vitro using human liver microsomes.
RESULTS
The mean mycophenolic acid AUC(0-9 h) in the sirolimus group was 44.9 mg h(-1) L(-1) (95% CI: 34.7-55.1), vs. 30.5 mg h(-1) L(-1) (95% CI: 25.4-35.6) in the ciclosporin group, corresponding to 1.5-fold dose-normalized difference (95% CI: 1.1-1.9; P < 0.05). In addition, the metabolite/mycophenolic acid AUC(0-9 h) ratios were significantly higher in patients cotreated with ciclosporin than with sirolimus, giving values of 1.8-fold (95% CI: 1.3-2.3; P = 0.0009), 2.6-fold (95% CI: 2.0-3.3; P < 0.0001) and 4.3-fold (95% CI: 2.6-6.0; P = 0.0016) for mycophenolic-acid-phenyl-glucuronide, mycophenolic-acid-acyl-glucuronide and mycophenolic-acid-phenyl-glucoside, respectively. In vitro, none of the immunosuppressive drugs tested inhibited mycophenolic acid metabolism.
CONCLUSION
Patients taking mycophenolate mofetil and sirolimus experience a higher exposure to mycophenolic acid and a lower exposure to mycophenolic acid metabolites than those being treated with mycophenolate mofetil and ciclosporin. This interaction is probably not caused by inhibition of mycophenolic acid glucuronidation or glycosylation, but is more likely to be due to the influence of ciclosporin on the excretion of mycophenolic acid metabolites into bile.
目的
比较霉酚酸与环孢素或西罗莫司联用时的药代动力学，并在体外研究环孢素、西罗莫司、他克莫司和依维莫司对霉酚酸代谢的潜在影响。
方法
在接受霉酚酸酯与环孢素（n = 19）或西罗莫司（n = 12）联合治疗的肾移植患者中，于移植后1个月测定霉酚酸、霉酚酸苯葡糖苷酸、霉酚酸酰基葡糖苷酸和霉酚酸苯葡糖苷的浓度-时间曲线。使用人肝微粒体在体外研究免疫抑制药物对霉酚酸葡糖醛酸化和糖基化的影响。
结果
西罗莫司组霉酚酸的平均AUC(0 - 9 h)为44.9 mg·h⁻¹·L⁻¹（95%可信区间：34.7 - 55.1），而环孢素组为30.5 mg·h⁻¹·L⁻¹（95%可信区间：25.4 - 35.6），相当于剂量标准化差异为1.5倍（95%可信区间：1.1 - 1.9；P < 0.05）。此外，环孢素联合治疗患者的代谢产物/霉酚酸AUC(0 - 9 h)比值显著高于西罗莫司联合治疗患者，霉酚酸苯葡糖苷酸、霉酚酸酰基葡糖苷酸和霉酚酸苯葡糖苷的比值分别为1.8倍（95%可信区间：1.3 - 2.3；P = 0.0009）、2.6倍（95%可信区间：2.0 - 3.3；P < 0.0001）和4.3倍（95%可信区间：2.6 - 6.0；P = 0.0016）。在体外，所测试的免疫抑制药物均未抑制霉酚酸代谢。
结论
与接受霉酚酸酯和环孢素治疗的患者相比，服用霉酚酸酯和西罗莫司的患者霉酚酸暴露量更高，霉酚酸代谢产物暴露量更低。这种相互作用可能不是由霉酚酸葡糖醛酸化或糖基化的抑制引起的，而更可能是由于环孢素对霉酚酸代谢产物向胆汁排泄的影响。
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