Rane A, Säwe J, Lindberg B, Svensson J O, Garle M, Erwald R, Jorulf H
J Pharmacol Exp Ther. 1984 May;229(2):571-6.
The kinetics of morphine in the rhesus monkey after i.v. or oral administration including the hepatic extraction ratio determined directly in the portal and hepatic veins were compared with the glucuronidation of morphine in liver microsomes from the same animals. The plasma half-lives varied between 102 and 202 min and the apparent volume of distribution was 2.68 to 3.15 l X kg b.wt.-1. The systemic blood clearance (9.2-21.3 ml X min-1 X kg b.wt.-1) was in the same range as the estimated hepatic blood clearance (9.7-23.9 ml X min-1 X kg b.wt.-1). After i.v. administration, the blood concentrations of morphine-3-glucuronide ( M3G ) were 8 to 11 times higher than those of morphine. The molar blood concentration ratio between morphine-6-glucuronide and M3G was 0.04 or less. The ratio between the metabolite levels in blood was similar to the relative formation rates for M3G and morphine-6-glucuronide in liver microsomal preparations (less than .039). The intrinsic hepatic metabolic clearance of morphine as estimated from the apparent enzyme kinetic constants Vmax and Km for the formation of the major M3G metabolite was used to predict the hepatic extraction ratio. The predicted values of the hepatic extraction ratio (0.09-0.14) were, however, underestimates of the experimentally determined hepatic extraction ratio, which varied between 0.61 and 0.74. This indicates that unknown factors in the liver microsomal glucuronidation preclude the use of enzyme kinetics parameters obtained in vitro for the prediction of the hepatic extraction ratio of morphine. For some drugs that are oxidized it has been shown previously that such prediction from in vitro data is possible.
将恒河猴静脉注射或口服吗啡后的动力学，包括直接在门静脉和肝静脉中测定的肝提取率，与同一动物肝微粒体中吗啡的葡萄糖醛酸化进行了比较。血浆半衰期在102至202分钟之间，表观分布容积为2.68至3.15升×千克体重-1。全身血液清除率（9.2 - 21.3毫升×分钟-1×千克体重-1）与估计的肝血液清除率（9.7 - 23.9毫升×分钟-1×千克体重-1）处于同一范围。静脉注射后，吗啡-3-葡萄糖醛酸苷（M3G）的血药浓度比吗啡高8至11倍。吗啡-6-葡萄糖醛酸苷与M3G的摩尔血药浓度比为0.04或更低。血液中代谢物水平的比例与肝微粒体制剂中M3G和吗啡-6-葡萄糖醛酸苷的相对形成率相似（小于0.039）。根据主要M3G代谢物形成的表观酶动力学常数Vmax和Km估计的吗啡肝内在代谢清除率用于预测肝提取率。然而，肝提取率的预测值（0.09 - 0.14）低于实验测定的肝提取率，后者在0.61至0.74之间变化。这表明肝微粒体葡萄糖醛酸化中的未知因素妨碍了使用体外获得的酶动力学参数来预测吗啡的肝提取率。对于一些被氧化的药物，先前已表明从体外数据进行这种预测是可能的。
