Szotáková Barbora, Skálová Lenka, Jílek Petr, Buchta Vladimír, Wsól Vladimír
Department of Biochemical Sciences, Research Centre LN00B125, Faculty of Pharmacy, Charles University, Heyrovského 1203, CZ-500 05 Hradec Králové, Czech Republic.
J Pharm Pharmacol. 2003 Jul;55(7):1003-11. doi: 10.1211/0022357021260.
The liver is the major site of drug metabolism in the body. However, many drugs undergo metabolism in extrahepatic sites and in the gut wall and lumen. In this study, the distribution and activity of reductases in rat that reduced potential cytostatic oracin to its principal metabolite 11-dihydrooracin (DHO) were investigated. The extension and stereospecificity of oracin reduction to DHO were tested in microsomal and cytosolic fractions from the liver, kidney, heart, lung and wall of small intestine, caecum and large intestine. Intestinal bacterial reduction of oracin was studied as well. The amount of DHO enantiomers was measured by HPLC with Chiralcel OD-R as chiral column. Reductive biotransformation of oracin was mostly stereospecific for (+)-DHO, but the enantiomeric ratio differed significantly among individual tissues and subcellular fractions (from 56% (+)-DHO in heart microsomes to 92% (+)-DHO in liver cytosol). Stereospecificity for (-)-DHO (60%) was observed in bacterial oracin reduction in the lumen of small intestine, caecum and large intestine. Shift of the (+)-DHO/(-)-DHO enantiomeric ratio from 90:10 (in liver subcellular fractions) to 60:40 (in-vivo) clearly demonstrated the importance of the contribution of extrahepatic metabolism to the total biotransformation of oracin to DHO.
肝脏是体内药物代谢的主要场所。然而，许多药物在肝外部位以及肠壁和肠腔内进行代谢。在本研究中，对大鼠体内将潜在的细胞生长抑制剂奥拉西因还原为其主要代谢物11-二氢奥拉西因（DHO）的还原酶的分布和活性进行了研究。在来自肝脏、肾脏、心脏、肺以及小肠、盲肠和大肠壁的微粒体和胞质组分中测试了奥拉西因还原为DHO的范围和立体特异性。还研究了肠道细菌对奥拉西因的还原作用。使用Chiralcel OD-R手性柱通过高效液相色谱法测量DHO对映体的量。奥拉西因的还原性生物转化对（+）-DHO大多具有立体特异性，但对映体比例在各个组织和亚细胞组分之间存在显著差异（从心脏微粒体中的56%（+）-DHO到肝脏胞质溶胶中的92%（+）-DHO）。在小肠、盲肠和大肠肠腔内的细菌对奥拉西因的还原中观察到对（-）-DHO的立体特异性（60%）。（+）-DHO/（-）-DHO对映体比例从90:10（在肝脏亚细胞组分中）转变为60:40（体内），清楚地证明了肝外代谢对奥拉西因向DHO的总生物转化的贡献的重要性。
