Déchelotte P, Sabouraud A, Sandouk P, Hackbarth I, Schwenk M
Allgemeine Pharmakologie, Medizinische Hochschule Hannover.
Drug Metab Dispos. 1993 Jan-Feb;21(1):13-7.
Orally administered morphine undergoes a considerable first-pass glucuronidation in animals and humans. However, the respective contribution of the gastrointestinal tract and the liver to the formation of the analgetically highly potent morphine-6-glucuronide (M6G) and the inactive morphine-3-glucuronide (M3G) is still debated. In this study, morphine uptake and biotransformation to M3G and M6G were compared in isolated cells from stomach, intestine, colon, and liver of the guinea pig. Morphine was taken up by all cell types in a time-dependent manner. There was evidence for a carrier-mediated accumulation in liver cells, but not in the other cell types. Morphine was glucuronidated to M3G by gastric, intestinal, colonic, and liver cells, and to M6G by all cell types excepted gastric cells. The M3G/M6G ratio averaged 3.5, 4.7, and 5.4 for colonic, intestinal, and liver cells, respectively. At low (1 microM) morphine concentration, glucuronidation rates for M3G and M6G in intestinal cells (88 and 20 pmol x mg protein-1 x hr-1, respectively) were similar to those in liver cells (133 and 12 pmol x mg protein-1 x hr-1, respectively). At high concentration (100 microM), rates of M3G and M6G formation in liver cells exceeded by 5- to 10-fold those of intestinal or colonic cells. In conclusion, the epithelium of the small and large intestine contributes with the liver to the formation of the active M6G; at the same time, the gastric, intestinal, and colonic epithelia are involved in the inactivation of morphine to M3G.
口服吗啡在动物和人体内会经历相当程度的首过葡萄糖醛酸化。然而，胃肠道和肝脏对镇痛效力很强的吗啡 -6- 葡萄糖醛酸苷（M6G）和无活性的吗啡 -3- 葡萄糖醛酸苷（M3G）形成的各自贡献仍存在争议。在本研究中，比较了豚鼠胃、小肠、结肠和肝脏的分离细胞中吗啡的摄取以及向 M3G 和 M6G 的生物转化。所有细胞类型均以时间依赖性方式摄取吗啡。有证据表明肝细胞中存在载体介导的积累，而其他细胞类型中则没有。胃、小肠、结肠和肝细胞将吗啡葡萄糖醛酸化生成 M3G，除胃细胞外的所有细胞类型都将其葡萄糖醛酸化生成 M6G。结肠、小肠和肝细胞的 M3G/M6G 比值分别平均为 3.5、4.7 和 5.4。在低吗啡浓度（1 μM）时，小肠细胞中 M3G 和 M6G 的葡萄糖醛酸化速率（分别为 88 和 20 pmol·mg 蛋白⁻¹·hr⁻¹）与肝细胞中的相似（分别为 133 和 12 pmol·mg 蛋白⁻¹·hr⁻¹）。在高浓度（100 μM）时，肝细胞中 M3G 和 M6G 的生成速率比小肠或结肠细胞的高出 5 至 10 倍。总之，小肠和大肠上皮与肝脏共同促成了活性 M6G 的形成；同时，胃、小肠和结肠上皮参与了吗啡向 M3G 的失活过程。
