HEPATIC ENZYME-ACTIVITY IS THE MAJOR FACTOR DETERMINING ELIMINATION RATE OF HIGH-CLEARANCE DRUGS IN CIRRHOSIS

The relative importance of alterations in hepatic enzyme activity, blood flow and drug binding to drug elimination in patients with liver disease remains controversial. In addition, liver disease appears to selectively impair drug oxidation pathways while leaving glucuronidation preserved. These studies using isolated perfused rat livers were designed to examine the effects of liver disease on the hepatic extraction and clearance and intrinsic clearance of morphine, a glucuronidated drug, and meperidine, an oxidized drug, under controlled blood flow and drug-binding conditions. We chose chronic carbon tetrachloride-induced cirrhosis as the liver disease. At a flow rate of 12 ml/min, the extraction of meperidine was reduced from 0.91 +/- 0.02 ml/min in controls to 0.76 +/- 0.04 ml/min (p < 0.05) in cirrhosis, hepatic clearance was reduced from 10.9 +/- 0.3 ml/min in controls to 9.15 +/- 0.48 ml/min (p < 0.05) in cirrhosis and intrinsic hepatic clearance was reduced from 179 +/- 35 ml/min in controls to 69 +/- 14 ml/min (p < 0.05) in cirrhosis. In contrast, for morphine we saw no significant changes: extraction ratio, 0.59 +/- 0.02 in controls and 0.49 +/- 0.04 in cirrhosis; hepatic clearance, 7.02 +/- 0.26 ml/min in controls and 6.04 +/- 0.42 ml/min in cirrhosis; and hepatic intrinsic clearance, 15.4 +/- 1.2 ml/min in controls and 13.9 +/- 2.3 ml/min in cirrhosis. Regression analysis of hepatic clearance vs. hepatic blood flow and hepatic clearance vs. hepatic intrinsic clearance demonstrate that in normal livers the elimination of both morphine and meperidine is mainly dependent on blood flow. However, in cirrhotic liver the decrease in hepatic clearance of meperidine is contributed to by reduction in intrinsic clearance or enzyme activity. This study demonstrates that hepatic enzyme activity becomes an important determinant of altered drug disposition in cirrhosis and confirms that glucuronidation is relatively preserved in liver disease.