Sandbaumhüter Friederike A, Thormann Wolfgang
Clinical Pharmacology Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
Electrophoresis. 2018 Jun;39(12):1478-1481. doi: 10.1002/elps.201800012. Epub 2018 Apr 3.
Glucuronidation catalyzed by uridine-5'-diphospho-glucuronosyl-transferases (UGTs) is the most important reaction in phase II metabolism of drugs and other compounds. O-glucuronidation is more common than N-glucuronidation. The anesthetic, analgesic and antidepressive drug ketamine is metabolized in phase I by cytochrome P450 enzymes to norketamine, hydroxynorketamine (HNK) diastereomers and dehydronorketamine (DHNK). Equine urine samples collected two hours after ketamine injection were treated with β-glucuronidase and analyzed with three enantioselective capillary electrophoresis assays. Concentrations of HNK diastereomers and norketamine were significantly higher in comparison to untreated urine and an increase of ketamine and DHNK levels was found in selected but not all samples. This suggests that O-glucuronides of HNK and N-glucuronides of the other compounds are formed in equines. N-glucuronidation of norketamine was studied in vitro with liver microsomes of different species and the single human enzyme UGT1A4. With equine liver microsomes (ELM) a stereoselective N-glucuronidation of norketamine was found that compares well to the results obtained with urines collected after ketamine administration. No reaction was observed with canine liver microsomes, human liver microsomes and UGT1A4. Incubation of ketamine and DHNK with ELM did not reveal any glucuronidation. Enantioselective CE is suitable to provide insight into the phase II metabolism of ketamine and its metabolites.
由尿苷-5'-二磷酸葡萄糖醛酸基转移酶（UGTs）催化的葡萄糖醛酸化是药物及其他化合物Ⅱ相代谢中最重要的反应。O-葡萄糖醛酸化比N-葡萄糖醛酸化更为常见。麻醉、镇痛和抗抑郁药物氯胺酮在Ⅰ相中通过细胞色素P450酶代谢为去甲氯胺酮、羟基去甲氯胺酮（HNK）非对映体和脱氢去甲氯胺酮（DHNK）。在注射氯胺酮两小时后采集的马尿样本用β-葡萄糖醛酸酶处理，并用三种对映体选择性毛细管电泳分析法进行分析。与未处理的尿液相比，HNK非对映体和去甲氯胺酮的浓度显著更高，并且在部分但并非所有样本中发现氯胺酮和DHNK水平有所升高。这表明在马体内形成了HNK的O-葡萄糖醛酸苷和其他化合物的N-葡萄糖醛酸苷。利用不同物种的肝脏微粒体和单一的人类酶UGT1A4在体外研究了去甲氯胺酮的N-葡萄糖醛酸化。在用马肝脏微粒体（ELM）进行实验时，发现去甲氯胺酮存在立体选择性N-葡萄糖醛酸化，这与氯胺酮给药后采集的尿液所得到的结果相当。在犬肝脏微粒体、人肝脏微粒体和UGT1A4实验中未观察到反应。氯胺酮和DHNK与ELM一起温育未显示出任何葡萄糖醛酸化。对映体选择性毛细管电泳适用于深入了解氯胺酮及其代谢物的Ⅱ相代谢。
