Relationship between the metabolism of antipyrine, hexobarbital and theophylline in patients with liver disease as assessed by a ‘cocktail’ approach

Abstract

Antipyrine (AP), hexobarbital (HB) and theophylline (TH) were administered simultaneously ('cocktail' design) to 24 patients with various types of liver disease. Clearance (Cl) of AP, HB and TH and formation clearance of the AP-metabolites 3-hydroxymethylantipyrine (HMA), norantipyrine (NORA) and 4-hydroxyantipyrine (OHA) were determined and correlation coefficients and orthogonal least-squares regression lines calculated between the clearance and formation clearance parameters. The results were compared with those obtained in a study in which the same 'cocktail' was administered to 26 healthy control subjects. In the patients ClAP, ClHB and ClTH were 23.0 +/- 14.3 ml min-1, 206 +/- 128 ml min-1 and 39.9 +/- 26.1 ml min-1 respectively. All values were considerably lower than those found in the control subjects. With regard to AP metabolism preferential impairment of NORA formation was observed. Relatively high correlation coefficients were found between ClAP, ClHB and ClTH, which suggests, like the results of orthogonal regression analysis, a strong correlation between total metabolism of these probe drugs. Therefore it is likely that impairment in oxidation in patients with liver disease not only leads to reduction in clearance but also to reduced substrate selectivity of cytochrome P-450 isozymes.