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

Authors

  • Naga Chalasani,

    1. Departments of Medicine and Indiana University School of Medicine, Indianapolis, IN
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  • J. Christopher Gorski,

    Corresponding author
    1. Departments of Medicine and Indiana University School of Medicine, Indianapolis, IN
    • Division of Clinical Pharmacology, Wishard Memorial Hospital, 1001 West 10th St., Room 320 OPW, Indianapolis, IN 46202. fax: (317) 630-8185
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  • Nilesh H. Patel,

    1. Radiology, Indiana University School of Medicine, Indianapolis, IN
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  • Stephen D. Hall,

    1. Departments of Medicine and Indiana University School of Medicine, Indianapolis, IN
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  • Raymond E. Galinsky

    Corresponding author
    1. Departments of Medicine and Indiana University School of Medicine, Indianapolis, IN
    2. School of Pharmacy, Purdue University, West Lafayette, IN.
    • Division of Clinical Pharmacology, Wishard Memorial Hospital, 1001 West 10th St., Room 320 OPW, Indianapolis, IN 46202. fax: (317) 630-8185
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Abstract

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 · h−1 · 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.

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