Serum aminotransferase activity as a predictor for estimation of total clearance of hepatically metabolized drugs in rats with acute hepatic failure

Abstract

The levels of serum aminotransferase activity, including aspartate aminotransferase (AST), in rats with acute hepatic failure at 24 h after an oral administration of CCl4 (0.01-0.5 ml/kg) were about 15-50 times higher (up to nearly 5000 IU/l) than those of vehicle control rats (about 85 IU/l). The values of total clearance (CLtot) of cyclosporin A, doxorubicin, tacrolimus and zonisamide in the CCl4-treated rats were decreased to about 1/2-1/3 of those in control rats. There were good correlations between AST activity and hepatic intrinsic clearance (CL int) (r=0.733-0.949) for the above drugs, as well as for chlorzoxazone, caffeine, lidocaine and tolbutamide after the intravenous administration of each drug in rats with acute hepatic failure. However, the slope of the linear regression equation, i.e., the ratio of decrease of CL int against increase of AST activity, differed markedly among these drugs. We found that there is a good correlation (r=0.953) between the values of the slope and the CLint of normal rats for these drugs, except for caffeine. In summary, the linear regression equation enables us to predict the decrease of CLtot in rats with acute hepatic failure to be predicted from the increase in serum AST activity. This approach may be useful as a guide for the dose modification of drugs for patients with acute hepatic failure. © 2006 Pharmaceutical Society of Japan.