Decrease in oral bioavailability of ciclosporin by intravenous pulse of methylprednisolone succinate in rats
Decrease in oral bioavailability of ciclosporin by intravenous pulse of methylprednisolone succinate in rats
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DOI：
10.1211/0022357044481
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发表时间：
2004-10-01
影响因子：
3.3
通讯作者：
Yamaji, A
中科院分区：
文献类型：
--
作者：
Konishi, H;Sumi, M;Yamaji, A
我们研究了大剂量甲基强的松龙对大鼠口服环孢素生物利用度的影响。为仿效甲基强的松龙冲击治疗的临床方案，甲基强的松龙的前体药物--甲基强的松龙琥珀酸钠(MPS)按重复剂量(66.3 mg·kg~(-1))静脉滴注，疗程3d。MPS冲击给药后，环孢素血药浓度-时间曲线下面积明显减少60%。基于我们先前的发现，在相同的甲基强的松龙冲击方案下，环孢素的整体人体清除量减少了约20%，口服环孢素的生物利用度降低的程度估计约为50%，这表明大剂量甲基强的松龙与口服环孢素之间存在药物相互作用，影响了吸收过程。在MPS处理的大鼠中，用罗丹明-123进行的原位外排实验表明，尽管三唑仑α-和4-羟化代谢探针对细胞色素P3A的代谢探针三唑仑的活性没有显著增加，但P-糖蛋白(P-gp)在小肠的反向转运功能显著增强。此外，在IMPS治疗中，作为环孢素胃肠吸收促进剂的分泌胆汁酸的数量也显著减少。为了直接评价MPS的吸收能力，在对照组和MPS处理组大鼠的小肠上进行了在体肠吸收试验。环孢素的肠道吸收显著减少，不仅在没有胆汁流动的情况下，而且在MPS治疗下也是如此，这很好地反映了甲基强的松龙冲击后环孢素在体内的药代动力学行为的变化。结果表明，MPS冲击给药可显著降低环孢素的生物利用度，其作用机制可能与增强小肠P-gp功能和减少胆汁分泌有关。
We examined the effects of high-dose methylprednisolone on the bioavailability of orally administered ciclosporin in rats. To emulate the clinical protocol of methylprednisolone pulse therapy, methylprednisolone sodium succinate (MPS), a prodrug of methylprednisolone, was intravenously administered as repeated doses (66.3 mg kg(-1)) for 3 days. The area under the blood ciclosporin concentration versus time curve after oral administration was significantly reduced by 60% by pulse treatment with MPS. Based on our previous finding that the total body clearance of ciclosporin was reduced by about 20% by the same methylprednisolone pulse protocol, the extent of reduction in the oral bioavailability of ciclosporin was estimated to be approximately 50%, indicating a drug interaction between high-dose methylprednisolone and orally administered ciclosporin, which affected the absorption process. In rats treated with MPS, an in-situ efflux experiment using rhodamine-123 demonstrated that the reverse transport function of P-glycoprotein (P-gp) in the small intestine was significantly enhanced, although there was no significant increase in the intestinal microsomal activity of triazolam alpha- and 4-hydroxylation, metabolic probes for CYP3A. In addition, a significant decrease was observed in the amount of secreted bile acids serving as an enhancer of gastrointestinal absorption of ciclosporin in IMPS treatment. To directly estimate the absorptive capacity, an in-situ absorption test was conducted using a closed-loop of small intestine in control and MPS-treated rats. Intestinal absorption of ciclosporin was significantly decreased, not only in the absence of bile flow but also by treatment with MPS, which well reflected the change in the in-vivo pharmacokinetic behaviour of ciclosporin after methylprednisolone pulsing. These results demonstrate that bioavailability of ciclosporin is markedly reduced by MPS pulse treatment, and the mechanism of this interaction was confirmed to involve enhancement of small-intestinal P-gp function and decrease in bile secretion.