Watari N, Iwai M, Kaneniwa N
J Pharmacokinet Biopharm. 1983 Jun;11(3):245-72. doi: 10.1007/BF01061867.
Pharmacokinetic studies of the fate of acetaminophen and its major metabolites, acetaminophen sulfate (AS) and acetaminophen glucuronide (AG), were made in rats. The rates of conjugate formation were calculated by deconvolution. The Michaelis-Menten equation gave maximum velocity and Michaelis constant (Km) values of 4.92 mumol/min/kg and 109 microM for AS formation, and 2.76 mumol/min/kg and 915 microM for AG formation. However, AG formation showed approximately first-order behavior in the present dose range because of its large Km value. The disposition of acetaminophen could be described by a two-compartment model with simultaneous first-order and Michaelis-Menten type elimination kinetics for AS formation. Curve fitting of the data based on this model was successfully done for doses of up to 1058 mumol/kg, suggesting that sulfation proceeds without depletion of sulfate in the blood at least up to this dose. The disposition of AS could be described by a two-compartment model and was apparently dose-independent over an 8-fold dose range. Although a slight dose dependence in the elimination of AG was suggested over a 16-fold dose range, for the purpose of the present study, it was assumed that the disposition of AG is approximately linear. The excretion of AS in the bile was negligibly small, whereas a considerable amount of AG was excreted into the bile. The results following intraduodenal injection of AS or AG indicated that AS or AG was hydrolyzed by the microflora and the liberated acetaminophen was reabsorbed, confirming enterohepatic circulation of the conjugates. This was consistent with the urinary metabolite excretion patterns observed after acetaminophen injection in normal and bile fistula rats. Based on the kinetic parameters obtained, the plasma concentrations of AS and AG after acetaminophen injection were simulated, and a fairly good agreement was obtained between calculated and observed values at the dose of 264.6 mumol/kg. Although the urinary metabolite excretion pattern differs from that of humans, the kinetic parameters obtained for rats were similar to those for humans in some respects, suggesting that the rat might be useful as a model animal to predict human data.
在大鼠体内进行了对乙酰氨基酚及其主要代谢产物硫酸对乙酰氨基酚（AS）和对乙酰氨基酚葡萄糖醛酸苷（AG）的药代动力学研究。通过反卷积计算结合物形成速率。米氏方程得出AS形成的最大速度和米氏常数（Km）值分别为4.92 μmol/分钟/千克和109 μM，AG形成的分别为2.76 μmol/分钟/千克和915 μM。然而，由于其Km值较大，AG形成在当前剂量范围内显示出近似一级动力学行为。对乙酰氨基酚的处置可用二室模型描述，AS形成具有同时的一级和米氏消除动力学。基于该模型对数据进行曲线拟合，对于高达1058 μmol/千克的剂量成功完成，表明至少在该剂量之前，硫酸化过程不会因血液中硫酸盐的耗尽而受到影响。AS的处置可用二室模型描述，并且在8倍剂量范围内明显与剂量无关。尽管在16倍剂量范围内提示AG消除存在轻微剂量依赖性，但就本研究而言，假定AG的处置近似呈线性。AS在胆汁中的排泄量可忽略不计，而相当数量的AG排泄到胆汁中。十二指肠内注射AS或AG后的结果表明，AS或AG被微生物群水解，释放出的对乙酰氨基酚被重新吸收，证实了结合物的肠肝循环。这与在正常大鼠和胆瘘大鼠中注射对乙酰氨基酚后观察到的尿代谢产物排泄模式一致。基于获得的动力学参数，模拟了注射对乙酰氨基酚后AS和AG的血浆浓度，在264.6 μmol/千克剂量下计算值与观察值之间获得了相当好的一致性。尽管尿代谢产物排泄模式与人类不同，但在某些方面大鼠获得的动力学参数与人类相似，表明大鼠可能作为预测人类数据的模型动物有用。
