Mistry M, Houston J B
Department of Pharmacy, University of Manchester, UK.
Drug Metab Dispos. 1987 Sep-Oct;15(5):710-7.
The glucuronidation of morphine, naloxone, and buprenorphine by the liver and intestine has been assessed both in vitro and in vivo in the rat. Using microsomes, Vmax/Km ratios were estimated as measures of intrinsic enzyme activity, and a wide range of ratios were obtained (500-fold). The ratio for the intestine was consistently less than for the liver, and the rank order of activities within each tissue was morphine less than naloxone less than buprenorphine. Using various routes of administration, plasma concentration-time profiles for each compound were determined and used to estimate hepatic and intestinal extraction ratios. These extraction ratios were dose-independent and more substantial for the liver than the intestine. For each tissue, buprenorphine and naloxone showed similar extraction, whereas morphine was less. Plasma binding and blood/plasma concentration ratios were determined, and perfusion models were used to calculate intrinsic clearance. This in vivo parameter of enzyme activity showed a wide range (200-fold), comparable to the spread of microsomal Vmax/Km ratios. Although the in vivo parameters consistently gave measures 10- to 30-fold higher than the in vitro parameters, the rank order was identical for the two sets. These data suggest that a comparative approach to correlate in vitro and in vivo data has advantages over the use of absolute drug characteristics.
在大鼠体内和体外对肝脏和肠道对吗啡、纳洛酮及丁丙诺啡的葡萄糖醛酸化作用进行了评估。利用微粒体，通过估算Vmax/Km比值来衡量内在酶活性，得到了广泛的比值范围（500倍）。肠道的比值始终低于肝脏，每个组织内的活性排序为吗啡低于纳洛酮低于丁丙诺啡。采用不同给药途径，测定了每种化合物的血浆浓度-时间曲线，并用于估算肝脏和肠道的提取率。这些提取率与剂量无关，肝脏的提取率比肠道更显著。对于每个组织，丁丙诺啡和纳洛酮表现出相似的提取率，而吗啡的提取率较低。测定了血浆结合率和血/血浆浓度比值，并使用灌注模型计算内在清除率。这种酶活性的体内参数显示出较宽的范围（200倍），与微粒体Vmax/Km比值的范围相当。虽然体内参数始终比体外参数高出10至30倍，但两组的排序相同。这些数据表明，将体外和体内数据相关联的比较方法比使用绝对药物特性具有优势。
