Disposition of aminopyrine, antipyrine, diazepam, and indocyanine green in patients with liver disease or on anticonvulsant drug therapy: diazepam breath test and correlations in drug elimination

The aim of this study was to determine to what extent hepatic elimination of various drugs correlates in control individuals, patients receiving anticonvulsants which stimulate the microsomal oxidizing system, and those with a variety of hepatobiliary diseases (hepatocellular disease, hepatic neoplasm, or cholestasis). Aminopyrine metabolism was measured by the ABT, diazepam elimination by a newly developed DBT as well as conventional plasma diazepam measurements, antipyrine clearance from drug analysis in saliva, and ICG clearance by its removal rate from plasma. The authors' data are as follows. First, DBT correlated well with diazepam half-life when all subject groups were combined (r = -0.65, p < 0.001). Second, anticonvulsant drugs enhanced the elimination of aminopyrine, diazepam, and antipyrine, but the degree of stimulation was significantly lower for aminopyrine; ICG elimination was not altered by anticonvulsant drugs. Third, the mean elimination for each drug tested in patients with hepatocellular and neoplastic liver diseases was depressed significantly and to a similar extent. In cholestasis, elimination of antipyrine and ICG but not of aminopyrine or diazepam was significantly depressed. Finally, there was no consistent correlation of the elimination of the 4 drugs tested in controls alone, and the correlation, although sometimes statistically significant, was only marginal (r = 0.30 to 0.67) in the combined hepatobiliary group alone. These overall data suggest that attempts to extrapolate pharmacokinetic data from 1 drug to another in individual subjects may be misleading.