Measurement of hepatic drug-metabolizing enxyme activity in man. Comparison of three different assays.

Abstract

Three parameters of hepatic drug metabolism, cytochrome P-450 (P-450) content, antipyrine metabolism and urinary excretion of glucaric acid (GA) were investigated in 161 patients who underwent diagnostic liver needle biopsy. P-450 and antipyrine metabolism, but not GA were related to histological changes in liver. All the parameters were significantly increased in subjects treated with enzyme-inducing drugs, the extent of induction being related to alterations in liver histology. The largest responses were seen in subjects with an intact liver and the smallest in those with hepatitis or cirrhosis. Therapy with inducers partly compensated for the impairement in drug metabolism caused by the disease process; thus, some patients with altered liver had normal values in the tests if they had been treated with inducers. There were significant correlations between in vivo and in vitro parameters of drug metabolism, but in the interpretation of data selection of the material and the parameters influenced the results. Thus, the antipyrine plasma clearance rate was directly related to P-450 and GA values, whereas the correlation between the latter and the drug half-life was non-linear. Also, comparison of selected groups of patients resulted in better correlations between the indices of drug metabolism than in the entire series. The results demonstrate that the overall picture of hepatic drug metabolism in man is largely determined by histological changes in the liver and by exposure to drugs, which are reflected differently in various assays of hepatic drug metabolism. Quantitative evaluation of these factors, and selection of the appropriate assay method, seem to be of importance in investigating hepatic drug metabolism in man.