Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: Effects of transjugular intrahepatic portosystemic shunts

Transjugular intrahepatic portosystemic shunt (TIPS) is performed to treat some complications of cirrhosis. This study investigated the effects of cir rhosis and TIPS on intestinal and hepatic cytochrome P450 3A (CYP3A) activi ty. Nine volunteers were cirrhotic patients with TIPS, 9 were cirrhotic con trols (matched for sex, age, etiology, and Child-Pugh class), and 9 were se x- and age-matched healthy volunteers. Simultaneous doses of midazolam were given intravenously (0.05 mg/kg) and orally (3 mg of [N-15(3)]midazolam). Peripheral and portal venous blood samples were assayed for midazolam and [ N-15(3)]midazolam. The systemic clearance of midazolam was significantly gr eater (P <.05) in healthy volunteers (0.42 +/- 0.10 L . h(-1) . kg(-1)) com pared with cirrhotic controls (0.20 +/- 0.05) and with cirrhotic patients w ith TIPS (0.21 +/- 0.09). Hepatic availability followed the same trend. The bioavailability of midazolam was significantly higher (P <.05) in cirrhoti c 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 avai lability 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 diminish ed intestinal CYP3A activity.