Rajnarayana Kandhagatla, Reddy Mada Sripal, Vidyasagar Jenugu, Krishna Devarakonda R
Drug Metabolism and Clinical Pharmacokinetics Division, University College of Pharmceutical Sciences, Kakatiya University, Warangal, AP, India.
Arzneimittelforschung. 2004;54(2):109-13. doi: 10.1055/s-0031-1296944.
A clinical study was undertaken in 12 healthy volunteers. At first, subjects received metronidazole (CAS 443-48-1; a substrate for cytochrome CYP3A4 and CYP2C9) alone at a dose of 400 mg every 8 h for 3 days. On day 4, blood and urine were collected at different time points and metronidazole levels were measured. After a washout period (> 10 half-lives) of one week silymarin (CAS 22888-70-6) was given at a daily dose of 140 mg for 9 days. From day 7 both silymarin (140 mg/day) and metronidazole (3 x 400 mg/day) were given till the 9th day. On day 10, blood and urine were collected as above and the levels of metronidazole and its metabolite were measured by HPLC. Administration of silymarin increased the clearence of metronidazole and its major metabolite, hydroxy-metronidazole (HM) by 29.51% and 31.90%, respectively, with a concomitant decrease in half-life, Cmax and AUC(0-48). Urinary excretions of acid-metronidazole (AM), HM as well as metronidazole in 48 h were decreased. The results indicate that silymarin might induce both intestinal P-glycoprotein and CYP3A4 upon multiple dose administration.
对12名健康志愿者进行了一项临床研究。起初，受试者单独接受甲硝唑（化学物质登记号443-48-1；细胞色素CYP3A4和CYP2C9的一种底物），剂量为每8小时400毫克，共3天。在第4天，在不同时间点采集血液和尿液，并测量甲硝唑水平。经过一周的洗脱期（>10个半衰期）后，给予水飞蓟宾（化学物质登记号22888-70-6），每日剂量为140毫克，共9天。从第7天起，同时给予水飞蓟宾（140毫克/天）和甲硝唑（3×400毫克/天），直至第9天。在第10天，按上述方法采集血液和尿液，并用高效液相色谱法测量甲硝唑及其代谢物的水平。水飞蓟宾的给药分别使甲硝唑及其主要代谢物羟基甲硝唑（HM）的清除率提高了29.51%和31.90%，同时半衰期、Cmax和AUC(0 - 48)降低。48小时内酸性甲硝唑（AM）、HM以及甲硝唑的尿排泄量减少。结果表明，多次给药后水飞蓟宾可能诱导肠道P-糖蛋白和CYP3A4。
