Plasma pharmacokinetics of butyrate after intravenous administration of sodium butyrate or oral administration of tributyrin or sodium butyrate to mice and rats
Plasma pharmacokinetics of butyrate after intravenous administration of sodium butyrate or oral administration of tributyrin or sodium butyrate to mice and rats
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DOI：
10.1007/s002800050922
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发表时间：
1999-06-01
影响因子：
3
通讯作者：
Eiseman, JL
中科院分区：
文献类型：
--
作者：
Egorin, MJ;Yuan, ZM;Eiseman, JL
目的：确定三丁酸甘油酯或丁酸钠给药小鼠和大鼠中达到的丁酸盐血浆浓度以及血浆丁酸盐浓度随时间的变化曲线。方法：雌性CD 2F1小鼠经口灌胃给予三丁酸甘油酯或经口灌胃给予丁酸钠。给予小鼠的三丁酸甘油酯口服剂量为3.1、5.2、7.8和10.3 g/kg。静脉注射丁酸钠剂量为0.31、0.62、0.94和1.25 g/kg。小鼠口服丁酸钠5 g/kg。随后，在雌性Sprague-Dawley大鼠中进行了类似的研究。大鼠经口灌胃给予三丁酸甘油酯，剂量为3.6、5.2或10.3 g/kg，或丁酸钠，剂量为500 mg/kg。通过气相色谱法测定血浆丁酸盐浓度。结果如下：在小鼠中，三丁酸甘油酯经口给药导致早在给药后5 min即可检测到血浆丁酸盐浓度，并在给药后15 - 60 min之间产生血浆丁酸盐浓度峰值。峰值血浆丁酸酯浓度随三丁酸甘油酯剂量的增加而成比例增加，但随着口服三丁酸甘油酯剂量的增加，血浆丁酸酯浓度-时间曲线下面积（AUC）的增加大于比例增加。三丁酸甘油酯剂量为10.3 g/kg时，血浆丁酸盐浓度达到峰值，约为1.75 mM，并在给药后10 - 60 min内保持大于或等于1 mM。然而，约10%的小鼠在接受该剂量治疗后急性死亡。在7.8 g/kg的三丁酸甘油酯剂量下，血浆丁酸盐浓度在给药后15 min达到约1 mM，并保持在0.8 - 1 mM之间，直至给药后60 min。接受该剂量给药的小鼠无急性死亡。给予5.2和3.1 g/kg三丁酸甘油酯剂量的小鼠在给药后45 min分别达到约0.9和0.5 mM的血浆丁酸盐浓度峰值。这些小鼠中的血浆丁酸盐浓度分别保持在0.1 mM以上，直至给药后120和90 min。丁酸钠的4次静脉给药产生的血浆浓度-时间曲线也表明非线性药代动力学，并通过具有饱和消除的一室模型进行了良好描述。记录的米氏常数（Km）和过程的最大速度（V-max）的值范围分别为1.02和5.65 mM以及0.60和1.82 mmol/min。记录的中央室容积（V-c）值在0.48和0.72 l/kg之间变化。在1.25 g/kg时，静脉注射丁酸钠产生的血浆丁酸盐浓度峰值为10.5 - 17.7 mM，血浆丁酸盐浓度保持在1 mM以上20 - 30 min。以5 g/kg经口给予小鼠丁酸钠，给药后15 min产生的血浆丁酸盐浓度峰值约为9 mM，给药后90 min血浆丁酸盐浓度超过1 mM。大鼠经口给予10.3 g/kg三丁酸甘油酯后，给药后75 min血浆丁酸浓度达到峰值，约为3 mM，给药后30 - 90 min丁酸浓度超过1 mM。5.2 g/kg和3.6 g/kg剂量在大鼠中产生的血浆丁酸盐浓度适当低于10.3 g/kg剂量产生的浓度，且无非线性证据。500 mg/kg的静脉注射剂量的丁酸钠产生的峰值血浆丁酸盐浓度在大鼠中约为II mM，并在血浆丁酸盐浓度的下降与饱和clearation.Conclusion后的时间是一致的：这些研究记录的能力，使用口服给药的三丁酸甘油酯，以实现在啮齿动物血浆中的丁酸盐的相关浓度。他们还记录了丁酸盐清除的非线性性质。这些数据被用于恶性肿瘤和血红蛋白病患者口服三丁酸甘油酯的临床试验设计。
Purpose: To define the plasma concentrations of butyrate achieved and the profile of plasma butyrate concentrations versus time in mice and rats treated with tributyrin or sodium butyrate. Methods: Female CD2F1 mice were treated with tributyrin by oral gavage or with sodium butyrate by i.v. bolus or oral gavage. Oral tributyrin doses delivered to mice were 3.1, 5.2, 7.8, and 10.3 g/kg. Intravenous sodium butyrate doses were 0.31, 0.62, 0.94, and 1.25 g/kg. Oral sodium butyrate was given to mice at 5 g/kg. Subsequently, similar studies were performed in female Sprague-Dawley rats. Rats were given tributyrin by oral gavage at doses of 3.6, 5.2, or 10.3 g/kg or sodium butyrate i.v. at a dose of 500 mg/kg. Plasma butyrate concentrations were determined by gas chromatography. Results: In mice, oral dosing with tributyrin resulted in detectable plasma butyrate concentrations as early as at 5 min after treatment and produced peak plasma butyrate concentrations at between 15 and 60 min after dosing. Peak plasma butyrate concentrations increased proportionally with increasing tributyrin dose, but as the oral tributyrin dose increased there was a greater than proportional increase in the area under the curve of plasma butyrate concentrations versus time (AUC). At a tributyrin dose of 10.3 g/kg, plasma butyrate concentrations peaked at approximately 1.75 mM and remained greater than or equal to 1 mM for between 10 and 60 min after dosing. However, approximately 10% of mice treated with this dose died acutely. At a tributyrin dose of 7.8 g/kg, plasma butyrate concentrations reached approximately I mM by 15 min after dosing and remained between 0.8 and 1 mM until 60 min after dosing. No mouse treated with this dose died acutely. Mice given tributyrin doses of 5.2 and 3.1 g/kg achieved peak plasma butyrate concentrations of approximately 0.9 and 0.5 mM, respectively, by 45 min after dosing. Plasma butyrate concentrations in these mice remained above 0.1 mM until 120 and 90 min after dosing, respectively. The four i.v. doses of sodium butyrate resulted in plasma concentration-time profiles that also indicated nonlinear pharmacokinetics and were well described by a one-compartment model with saturable elimination. Values recorded for the Michaelis-Menten constant (K-m) and the maximal velocity of the process (V-max) ranged between 1.02 and 5.65 mM and 0.60 and 1.82 mmol/min, respectively. Values noted for the volume of the central compartment (V-c) varied between 0.48 and 0.72 1/kg. At 1.25 g/kg, i.v. sodium butyrate produced peak plasma butyrate concentrations of 10.5-17.7 mM, and plasma butyrate concentrations remained above 1 mM for 20-30 min. Sodium butyrate delivered orally to mice at 5 g/kg produced peak plasma butyrate concentrations of approximately 9 mM at 15 min after dosing and plasma butyrate concentrations exceeding 1 mM for 90 min after dosing. In rats the 10.3-g/kg oral dose of tributyrin produced peak plasma butyrate concentrations of approximately 3 mM by 75 min after dosing and butyrate concentrations excedding 1 mM from 30 to 90 min after dosing. The plasma butyrate concentrations produced in rats by 5.2- and 3.6-g/kg doses were appropriately lower than those produced by the 10.3-g/kg dose, and there was no evidence of nonlinearity. The 500-mg/kg i.v. dose of sodium butyrate produced peak plasma butyrate concentrations in rats of approximately II mM, and the decline in plasma butyrate concentrations with time after dosing was consistent with saturable clearance.Conclusion: These studies document the ability to use oral administration of tributyrin to achieve pharmacologically relevant concentrations of butyrate in rodent plasma. They also document the nonlinear nature of butyrate clearance. These data are being used in the design of clinical trials of oral tributyrin in patients with malignancies and hemoglobinopathies.