Blood Distribution and Single‐Dose Pharmacokinetics of Leflunomide
Blood Distribution and Single‐Dose Pharmacokinetics of Leflunomide
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来氟米特的血液分布和单剂量药代动力学
DOI：
10.1097/00007691-199510000-00004
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发表时间：
1995
影响因子：
2.5
通讯作者：
R. Yatscoff
中科院分区：
文献类型：
--
作者：
J. Lucien;V. Dias;D. Legatt;R. Yatscoff
来氟米特（HWA 486，LEF）是一种新型异恶唑衍生物，具有强效免疫抑制作用。LEF在吸收后转化为其活性代谢产物（A77 1726）。目前，LEF的血液分布和药代动力学尚未见报道。这些信息在确定用于分析的适当介质和最佳免疫抑制剂给药方案方面将证明是非常宝贵的。在本研究中，发现A77 1726在0.4至100 mg/L的所有试验浓度下主要与血浆中的无脂蛋白部分相关（>95%）。仅在最高检测浓度（100 mg/L）下，在血浆游离组分中发现可检测水平的A77 1726（0.34 ± 0.18 mg/L）（通过HPLC分析）。A77 1726单次给药（i. v.）和HWA 486（p.o.）在5只健康新西兰白色家兔中进行了研究。A77 1726 i.v.和HWA 486 p.o.给药时间分别为3.88 ± 2.3和3.18 ± 1.6 h。两种给药途径的分布体积表明组织中的分布最小（Vdssp.o. = 0.14 ± 0.03 L/kg和Vdssi.v. = 0.09 ± 0.02 L/kg）。A77 1726的平均滞留时间在口服LEF后更长（MRT p. o. = 10.54 ± 2.6 h，MRTi.v. = 6.76 ± 1.0 h）。相同的曲线下面积表明生物利用度为100%（AUCp.o. = 421.16 ± 204.5 mg ± h/L和AUCi.v. = 399.75 ± 126.9 mg ± h/L）。
Summary Leflunomide (HWA 486, LEF) is a novel isoxazole derivative with potent immunosuppressive properties. LEF is converted to its active metabolite (A77 1726) after absorption. Presently, the blood distribution and pharmacokinetics of LEF have not been reported. Such information would prove invaluable in determining the appropriate medium for analysis and optimal immunosuppressive dosing regimes. In this study, A77 1726 was found to be primarily associated (>95%) with the lipoprotein free fraction of plasma at all tested concentrations ranging from 0.4 to 100 mg/L. Detectable levels of A77 1726 (0.34 ± 0.18 mg/L), analyzed by HPLC, were found in the plasma free fraction only at the highest tested concentration (100 mg/L). Single-dose phar-macokinetics of A77 1726 (i.v.) and HWA 486 (p.o.) were investigated in five healthy New Zealand white rabbits. The half-lives (t1/2) of A77 1726 i.v. and HWA 486 p.o. administration were 3.88 ± 2.3 and 3.18 ± 1.6 h, respectively. The volume of distribution by both routes of administration indicates minimal distribution into tissues (Vdssp.o. = 0.14 ± 0.03 L/kg and Vdssi.v. = 0.09 ± 0.02 L/kg). The mean residence time of A77 1726 was greater after oral administration of LEF (MRTp.o. = 10.54 ± 2.6 h and MRTi.v. = 6.76 ± 1.0 h). Identical areas under the curve suggest bioavailability was 100% (AUCp.o. = 421.16 ± 204.5 mg ± h/L and AUCi.v. = 399.75 ± 126.9 mg ± h/L).