Tateishi T, Soucek P, Caraco Y, Guengerich F P, Wood A J
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.
Biochem Pharmacol. 1997 Jan 10;53(1):111-6. doi: 10.1016/s0006-2952(96)00693-4.
Colchicine disposition involves both active biliary and renal excretion of parent drug, and at least in mammals a substantial fraction undergoes hepatic demethylation prior to excretion. We investigated the biotransformation of [3H]colchicine in a panel of microsomal preparations obtained from sixteen human liver samples. The production rate of the main metabolites of colchicine's 3-demethylcolchicine (3DMC) and 2-demethylcolchicine (2DMC), was linear in relation to incubation time, cytochrome (P450) content, and substrate concentration. Following the incubation of colchicine (5 nM) with microsomes in the presence of an NADPH-generating system for 60 min, 9.8% and 5.5% of the substrate were metabolized to 3DMC and 2DMC, respectively. The formation rate of colchicine metabolites exhibited a marked variation between the different microsomal preparations. The formation rates of both colchicine metabolites were correlated significantly with nifedipine oxidase activity, a marker of CYP3A4 activity (r = 0.96, P < 0.001), but not with the metabolic markers of CYP2A6, CYP2C19, CYP2C9, CYP2D6, and CYP2E1 activities. Chemical inhibition of CYP3A4 by preincubation with gestodene (40 microM) or troleandomycin (40 microM) reduced the formation of 3DMC and 2DMC by 70 and 80%, respectively, whereas quinidine, diethyldithiocarbamate, and sulfaphenazole had no inhibitory effect. Similarly, antibodies raised against CYP3A4 almost completely abolished colchicine demethylation and nifedipine oxidase activity, but preimmune IgG had no effect. In conclusion, colchicine was metabolized to 3DMC and 2DMC by human liver microsomes. The production of colchicine metabolites was mediated by CYP3A4, and its rate varied greatly between microsomal preparations obtained from different liver samples. The coadministration of colchicine with known inhibitors or substrates of CYP3A4 may inhibit colchicine metabolism, resulting in concentration-related toxicity.
秋水仙碱的处置涉及母体药物的胆汁和肾脏主动排泄，并且至少在哺乳动物中，很大一部分在排泄前会经历肝脏去甲基化。我们在从16个人类肝脏样本中获得的一组微粒体制剂中研究了[3H]秋水仙碱的生物转化。秋水仙碱的主要代谢产物3-去甲基秋水仙碱（3DMC）和2-去甲基秋水仙碱（2DMC）的生成速率与孵育时间、细胞色素（P450）含量和底物浓度呈线性关系。在存在NADPH生成系统的情况下，将秋水仙碱（5 nM）与微粒体孵育60分钟后，分别有9.8%和5.5%的底物代谢为3DMC和2DMC。秋水仙碱代谢产物的形成速率在不同的微粒体制剂之间表现出显著差异。两种秋水仙碱代谢产物的形成速率均与硝苯地平氧化酶活性（CYP3A4活性的标志物）显著相关（r = 0.96，P < 0.001），但与CYP2A6、CYP2C19、CYP2C9、CYP2D6和CYP2E1活性的代谢标志物无关。通过与孕二烯酮（40 microM）或醋竹桃霉素（40 microM）预孵育对CYP3A4进行化学抑制，分别使3DMC和2DMC的形成减少了70%和80%，而奎尼丁、二乙基二硫代氨基甲酸盐和磺胺苯唑没有抑制作用。同样，针对CYP3A4产生的抗体几乎完全消除了秋水仙碱的去甲基化和硝苯地平氧化酶活性，但免疫前IgG没有作用。总之，秋水仙碱被人肝微粒体代谢为3DMC和2DMC。秋水仙碱代谢产物的产生由CYP3A4介导，其速率在从不同肝脏样本获得的微粒体制剂之间有很大差异。秋水仙碱与已知的CYP3A4抑制剂或底物合用时，可能会抑制秋水仙碱的代谢，导致与浓度相关的毒性。
