Serum Aminotransferase Activity as a Predictor for Estimation of Total Clearance of Hepatically Metabolized Drugs in Rats with Acute Hepatic Failure

Abstract

In treating patients with hepatic failure, it is necessary to set an appropriate drug dosing schedule to take into account of their altered drug disposition kinetics. However, little work has been done to estimate the decrease of total clearance (CL tot ) in relation to the degree of residual hepatic function. Therefore, there is great need for a suitable marker to quantitatively predict the hepatic metabolic capacity in patients with hepatic failure.In humans, there are five predominant families of cytochrome P450 (CYP) species, CYP1A, CYP2C, CYP2D, CYP2E and CYP3A; all of the isoforms differ in their patterns of drug-metabolizing activity, 1) and the amounts of the isoforms in the liver are altered under conditions of hepatic failure.2) The drug-metabolizing activity of the liver may be evaluated on the basis of the correlation between the clearance and the ratio of the metabolite(s) to unchanged drug after the administration of specific inhibitors of various CYP isoforms.Recently, there have been many reports on the expression levels of CYP isoform mRNAs in human liver collected by hepatobiopsy, but no clear correlation has been found between expression levels and the degree of hepatic failure. 3,4) Finnstrom et al. reported that the expression of CYP mRNA in liver is different from that in blood; therefore, blood cannot serve as a surrogate organ for assessment of the expression of the CYP genes in liver.5) Panduro et al. 6) reported that liver regeneration and fibrosis are related to g-carboxylase activity, which is associated with a prolongation of prothrombin time in plasma in rats treated with CCl 4 . Clinically, indocyanine green is commonly used to assess hepatic function. 7)However, none of these procedures appears to be suitable for predicting the decrease in hepatic metabolic activity in patients with hepatic failure.It has been proposed that the drug-metabolizing activity of the liver can be estimated by means of pharmacokinetic analysis after the administration of various probe drugs for CYP isoforms. [8][9][10][11] Matsuo et al. demonstrated that there is a correlation between the CL tot of cyclosporine and the grade severity of liver disease by Child-Pugh classification in patients with hepatitis. 12) However, it is not easy to utilize these approaches to determine the degree of residual hepatic metabolizing ability in patients, as is also the case with creatinine clearance in patients with renal failure.We previously reported that there is a good correlation between mRNA expression and enzyme activity of various CYP isoforms in the livers of rats with acute hepatic failure induced by various doses of CCl 4 . 13) In that study, we also found a good negative correlation between serum aminotransferase activity (AST) and the hepatic activity of each CYP isoform, though the degree of decrease of CL tot varied markedly among CYP isoforms.Here, we present a novel procedure to predict the decrease of CL tot , including that for unknown drugs, based on an increase in serum AST activity in rats with ac...

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