Disposition of methylprednisolone and its sodium succinate prodrug in vivo and in perfused liver of rats: nonlinear and sequential first-pass elimination.
Disposition of methylprednisolone and its sodium succinate prodrug in vivo and in perfused liver of rats: nonlinear and sequential first-pass elimination.
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甲基强的松龙及其琥珀酸钠前药在体内和大鼠灌注肝脏中的处置：非线性和顺序首过消除。
DOI：
10.1002/jps.2600800502
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发表时间：
1991
影响因子：
3.8
通讯作者：
Jusko,WJ
中科院分区：
文献类型：
--
作者：
Kong,AN;Jusko,WJ
本实验研究了甲基强的松龙（MP）及其前体药物琥珀酸酯（MS）在大鼠体内和原位（灌流肝）的分布。体内研究包括静脉和经口给予10或50 mg/kg两种形式的MP，而肝脏灌注涉及初始灌注液浓度为5和25 μg/mL的任一化合物。通过HPLC测量类固醇浓度。在完整大鼠中，两种化合物的清除率（CL）值均较高，为肝血浆流量的两倍，高剂量给药后降低一半，表明非线性动力学。MS和MP的分布容积基本上随剂量而恒定。发现MP从静脉注射MS（52-55%）和口服剂量（10%）中的利用度不完全。在低剂量下发生MP的广泛肝提取（84%），但在高剂量下降低至48%，支持高CL和非线性的体内观察结果。MS的提取率也很高（83%），但MP的利用率很低（8%）。将MS和MP数据拟合至序贯首过模型，得到MS代谢为MP的平均分数值为0.22。因此，前药MS和活性代谢产物MP在大鼠中表现出全身和肝脏非线性，IV MS中MP的低利用度部分归因于序贯首过消除。这一因素在大鼠中比在其他物种中更为广泛。
The disposition of methylprednisolone (MP) and its prodrug succinate ester, methylprednisolone sodium succinate (MS), were examined both in vivo and in situ (perfused livers) in rats. In vivo studies included iv and oral dosing of 10 or 50 mg/kg of MP in both forms, while liver perfusion involved initial perfusate concentrations of 5 and 25 μg/mL of either compound. Steroid concentrations were measured by HPLC. In the intact rat, clearance (CL) values of both compounds were high, twice the hepatic plasma flow, and decreased by one‐half after the high dose, indicating nonlinear kinetics. The volumes of distribution of MS and MP were essentially constant with dose. Incomplete availability of MP from iv MS (52–55%) and from the oral dose (10%) was found. Sequential first‐pass metabolism was investigated in situ. Extensive hepatic extraction of MP (84%) occurred at the low dose, but decreased to 48% at the high dose, supporting in vivo observations of high CL and nonlinearity. Extraction of MS was also high (83%), but MP availability was slight (8%). The MS and MP data were fitted to a sequential first‐pass model yielding an average fraction of MS metabolized‐to‐MP value of 0.22. The prodrug MS and the active metabolite MP thus demonstrate both systemic and hepatic nonlinearity in rats, and the low availability of MP from iv MS was due, in part, to sequential first‐pass elimination. This factor is more extensive in rats than in other species.
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DOI：
--
发表时间：
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期刊：
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影响因子：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
W. Jusko
DOI：
--
发表时间：
1973
期刊：
影响因子：
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作者：
I. Bartošek;A. Guaitani;L. L. Miller
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L. L. Miller