Konishi Hiroki, Sumi Masaki, Shibata Nobuhito, Takada Kanji, Minouchi Tokuzo, Yamaji Akira
Department of Hospital Pharmacy, Shiga University of Medical Science, Otsu, Japan.
J Pharm Pharmacol. 2004 Apr;56(4):477-83. doi: 10.1211/0022357023114.
We examined the effects of high-dose methylprednisolone (MP) on the disposition of ciclosporin (CsA) and hepatic microsomal CYP3A activity using rats. Methylprednisolone sodium succinate (MPS), a prodrug of MP, was intravenously administered as repeated doses (66.3 mg kg(-1)) for 3 days or as a single dose. In MP-treated rats, a significant increase was observed in the total body clearance (CL(tot)) and elimination rate constant (Ke) of intravenously administered CsA. The enzyme activities of triazolam hydroxylations and erythromycin N-demethylation in hepatic microsomes were also enhanced by about 50% by MP treatment, suggesting that the alteration in the CsA pharmacokinetics was due to significant induction of the hepatic CYP3A responsible for the metabolic conversion of CsA. In contrast, no significant changes in the values of CL(tot) and Ke were found following a single treatment with MP. On the other hand, MP inhibited the CYP3A-mediated triazolam hydroxylations in a concentration-dependent manner. The difference between the in-vivo and in-vitro inhibitory behaviours of MP was attributed to the rapid elimination of MP after biotransformation from MPS because the plasma MP concentration decreased with a half-life of 15 min immediately after reaching a level close to the inhibition constant for the triazolam 4-hydroxylation reaction (32.4 microM). Although there is a general consideration that MP cannot act as an enzyme inducer at maintenance doses, the present results strongly suggest that high-dose MP is likely to interact pharmacokinetically with CsA by inducing hepatic CYP3A. These results may provide basic explanations for the clinical experience that blood CsA levels are reduced during MP pulse therapy.
我们使用大鼠研究了大剂量甲泼尼龙（MP）对环孢素（CsA）处置及肝微粒体CYP3A活性的影响。甲泼尼龙琥珀酸钠（MPS）作为MP的前体药物，以重复剂量（66.3 mg kg⁻¹）静脉注射3天或单次给药。在MP处理的大鼠中，静脉注射CsA后的全身清除率（CL(tot)）和消除速率常数（Ke）显著增加。MP处理还使肝微粒体中三唑仑羟化和红霉素N-去甲基化的酶活性增强了约50%，这表明CsA药代动力学的改变是由于负责CsA代谢转化的肝CYP3A被显著诱导。相比之下，单次MP处理后CL(tot)和Ke的值未发现显著变化。另一方面，MP以浓度依赖性方式抑制CYP3A介导的三唑仑羟化。MP体内和体外抑制行为的差异归因于MPS生物转化后MP的快速消除，因为血浆MP浓度在达到接近三唑仑4-羟化反应抑制常数（32.4 microM）的水平后立即以15分钟的半衰期下降。尽管一般认为维持剂量的MP不能作为酶诱导剂，但目前的结果强烈表明大剂量MP可能通过诱导肝CYP3A与CsA发生药代动力学相互作用。这些结果可能为MP脉冲治疗期间血CsA水平降低的临床经验提供基本解释。
