Chalasani N, Gorski J C, Patel N H, Hall S D, Galinsky R E
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Hepatology. 2001 Dec;34(6):1103-8. doi: 10.1053/jhep.2001.29306.
Transjugular intrahepatic portosystemic shunt (TIPS) is performed to treat some complications of cirrhosis. This study investigated the effects of cirrhosis and TIPS on intestinal and hepatic cytochrome P450 3A (CYP3A) activity. Nine volunteers were cirrhotic patients with TIPS, 9 were cirrhotic controls (matched for sex, age, etiology, and Child-Pugh class), and 9 were sex- and age-matched healthy volunteers. Simultaneous doses of midazolam were given intravenously (0.05 mg/kg) and orally (3 mg of [15N3]midazolam). Peripheral and portal venous blood samples were assayed for midazolam and [15N3]midazolam. The systemic clearance of midazolam was significantly greater (P <.05) in healthy volunteers (0.42 +/- 0.10 L x h(-1) x kg(-1)) compared with cirrhotic controls (0.20 +/- 0.05) and with cirrhotic patients with TIPS (0.21 +/- 0.09). Hepatic availability followed the same trend. The bioavailability of midazolam was significantly higher (P <.05) in cirrhotic patients with TIPS (0.76 +/- 0.20) compared with cirrhotic controls (0.27 +/- 0.14) and with healthy volunteers (0.30 +/- 0.10). The intestinal availability was significantly greater (P <.05) in cirrhotic patients with TIPS (0.83 +/- 0.17) compared with cirrhotic controls (0.32 +/- 0.16) and with healthy volunteers (0.42+/-0.15). As expected, hepatic CYP3A activity was reduced in cirrhosis. However, in cirrhotic patients with TIPS, there was a marked loss in first-pass metabolism of midazolam as a result of diminished intestinal CYP3A activity.
经颈静脉肝内门体分流术（TIPS）用于治疗肝硬化的一些并发症。本研究调查了肝硬化和TIPS对肠道及肝脏细胞色素P450 3A（CYP3A）活性的影响。9名志愿者为接受TIPS治疗的肝硬化患者，9名是肝硬化对照者（在性别、年龄、病因及Child-Pugh分级方面匹配），9名是在性别和年龄上匹配的健康志愿者。同时静脉注射（0.05 mg/kg）和口服（3 mg [15N3]咪达唑仑）咪达唑仑。检测外周血和门静脉血样本中的咪达唑仑及[15N3]咪达唑仑。与肝硬化对照者（0.20±0.05）及接受TIPS治疗的肝硬化患者（0.21±0.09）相比，健康志愿者中咪达唑仑的全身清除率显著更高（P<0.05）（0.42±0.10 L·h-1·kg-1）。肝脏利用率也呈现相同趋势。与肝硬化对照者（0.27±0.14）及健康志愿者（0.30±0.10）相比，接受TIPS治疗的肝硬化患者中咪达唑仑的生物利用度显著更高（P<0.05）（0.76±0.20）。与肝硬化对照者（0.32±0.16）及健康志愿者（0.42±0.15）相比，接受TIPS治疗的肝硬化患者的肠道利用率显著更高（P<0.05）（0.83±0.17）。正如预期，肝硬化时肝脏CYP3A活性降低。然而，在接受TIPS治疗的肝硬化患者中，由于肠道CYP3A活性降低，咪达唑仑的首过代谢明显减少。
