title: Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: effects of transjugular intrahepatic portosystemic shunts.
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 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.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: N
authors.initials: N
authors.lastname: Chalasani
authors.forename: J C
authors.initials: JC
authors.lastname: Gorski
authors.forename: N H
authors.initials: NH
authors.lastname: Patel
authors.forename: S D
authors.initials: SD
authors.lastname: Hall
authors.forename: R E
authors.initials: RE
authors.lastname: Galinsky
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000601:surgery*; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D019168:Portasystemic Shunt, Transjugular Intrahepatic; D012016:Reference Values; D013997:Time Factors
chemical_list: D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam