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.

Liver blood flow, antipyrine clearance, and antipyrine metabolite formation clearance in patients with chronic active hepatitis and alcoholic cirrhosis.

“…Indocyanine green (ICG) and bromsulphthalein (BSP) both have high hepatic extraction ratios in subjects with normal liver function, and their clearance rates have been used as surrogate measures of liver blood flow [1][2][3][4]. Intrinsic clearance associated with the activity of the cytochrome P-450 enzyme system has been assessed from antipyrine clearance [22][23][24] and, more recently, from the formation clearances to antipyrine metabolites [9][10][11][12].…”

“…Orthogonal regression was chosen because both x and y values are subject to measurement error [12]. Logarithmic transformations of metabolite formation clearances and liver blood flows were used in the orthogonal regressions because the metabolite formation clearances and liver blood flows had different variances [12]. Pearson correlation coefficients were also computed.…”

“…Orthogonal regression was used to determine relationships between metabolite formation clearances and also betwen metabolite formation clearances and liver blood flows. Orthogonal regression was chosen because both x and y values are subject to measurement error [12]. Logarithmic transformations of metabolite formation clearances and liver blood flows were used in the orthogonal regressions because the metabolite formation clearances and liver blood flows had different variances [12].…”

“…[17,18]. The formation clearance to each antipyrine metabolite was computed from the product of the fraction of the antipyrine dose eliminated as metabolite in the urine and antipyrine clearance [11,12]. Body surface area was calculated using the method of DuBois & DuBois [19].…”

“…Duplex scanning is a relatively new noninvasive technique that can be used to measure liver blood flow through the hepatic artery and branches of the portal and hepatic veins [5][6][7][8]. Antipyrine clearance and the formation clearances to its metabolites have been used to measure P-450 hepatic drug metabolism capacity [9][10][11][12]. The purpose of this study was to measure liver blood flow in cirrhotic and hepatitis patients using a noninvasive, direct measurement technique and to determine if cirrhosis and hepatitis affect liver blood flow, antipyrine pharmacokinetics, and the formation clearances of antipyrine to its metabolites in man.…”