Quantitation of intrinsic drug-metabolizing capacity in human liver biopsy specimens: Support for the intact-hepatocyte theory

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Abstract

Hepatic drug metabolism is decreased in patients with severe liver disease, but it is unclear to what extent this is due to altered hepatic blood flow or reduced intrinsic metabolic capacity. In this study we quantitated in needle-biopsy specimens the intrinsic capacity of liver tissue from 67 patients with mild liver disease (n = 36), chronic active hepatitis (n = 16) and cirrhosis (n = 15) to metabolize two model compounds in vitro. Hydroxylation of the low-extraction drug bufuralol resulted in the formation of 251 ± 25 nmol 1′OH-bufuralol/gm wet wt/hr in mildly diseased liver tissue and was significantly (p <0.01) reduced in liver tissue exhibiting chronic active hepatitis (166 ± 23 nmol/gm wet wt/hr) and cirrhosis (124 ± 21 nmol/gm wet wt/hr). The formation rates of monoethylglycinexylidide, the main metabolite of the high-extraction drug lidocaine, varied widely and were not significantly different among the three groups. To relate the drug-metabolizing capacity to the hepatocyte content of liver tissue, morphometrical study was performed in the biopsy pieces originally submitted. The metabolic activity of each biopsy piece was then related to the fractional volume of hepatocytes it was calculated to contain. In mildly diseased liver tissue 355 ± 35 nmol 1′OH-bufuralol/ml hepatocytes x hr or 12.4 ± 1.0 μmol monoethylglycinexylidide/ml hepatocytes x hr–and in cirrhotic liver tissue 306 ± 49 nmol 1′OH-bufuralol/ml hepatocytes x hr or 15.3 ± 3.0 μmol monoethylglycinexylidide/ml hepatocytes x hr–were formed, respectively, and these differences were not significant. In summary, we found that impairment of the metabolic function of cirrhotic biopsy pieces is due to a loss of hepatocytes, whereas the metabolic activity of the remaining hepatocytes is preserved. We conclude that these findings support the intact-hepatocyte hypothesis. (HEPATOLOGY 1991;13:475–481.)

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