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

Naga Chalasani, J. Christopher Gorski, Nilesh H. Patel, Stephen D. Hall, Raymond E. Galinsky

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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] .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.

Original languageEnglish
Pages (from-to)1103-1108
Number of pages6
JournalHepatology
Volume34
Issue number6
DOIs
StatePublished - 2001

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Transjugular Intrahepatic Portasystemic Shunt
Cytochrome P-450 CYP3A
Midazolam
Fibrosis
Liver
Healthy Volunteers
Biological Availability
Volunteers

ASJC Scopus subject areas

  • Hepatology

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Hepatic and intestinal cytochrome P450 3A activity in cirrhosis : Effects of transjugular intrahepatic portosystemic shunts. / Chalasani, Naga; Gorski, J. Christopher; Patel, Nilesh H.; Hall, Stephen D.; Galinsky, Raymond E.

In: Hepatology, Vol. 34, No. 6, 2001, p. 1103-1108.

Research output: Contribution to journalArticle

Chalasani, Naga ; Gorski, J. Christopher ; Patel, Nilesh H. ; Hall, Stephen D. ; Galinsky, Raymond E. / Hepatic and intestinal cytochrome P450 3A activity in cirrhosis : Effects of transjugular intrahepatic portosystemic shunts. In: Hepatology. 2001 ; Vol. 34, No. 6. pp. 1103-1108.
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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] .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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AU - Galinsky, Raymond E.

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