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.