Correlation between the in vivo metabolism of hexobarbital and antipyrine in rats

Two model substrates for oxidative hepatic enzyme activity, viz. hexobarbital (HB) and antipyrine (AP), were given simultaneously to rats by the oral route of administration. Blood concentrations of HB and AP were measured simultaneously by a gas chromatographic method and the urinary excretion of six metabolites arising from AP and HB also was determined; norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine (HMA) by high-performance liquid chromatography; 3'-hydroxyhexobarbital, 3'-ketohexobarbital and 1,5-dimethylbarbituric acid by gas-liquid chromatography. The apparent intrinsic clearances of HB (CL*int,HB) and AP (CL*int,AP) and the clearance for production of the various metabolites were correlated in an attempt to establish whether HB and AP have metabolic pathways mediated by the same or very similar forms of cytochrome P-450. In order to create broadly ranging and evenly distributed clearance values, 3-methylcholanthrene (3-MC)- and phenobarbital (PB) pretreated rats were employed in conjunction with a control group of untreated animals. CL*int,HB and CL*int,AP were both increased by PB pretreatment, but 3-MC-pretreatment increased CL*int,AP, whereas CL*int,HB was decreased. CL*int,HB and CL*int,AP were found to correlate poorly, when all groups were taken into consideration (r = -0.08). The formation of AP-metabolites was inducible by both PB and 3-MC, and good correlations between rates of formation of AP-metabolites and CL*int,HB and CL3'-hydroxy-HB + 3'-keto-HB were obtained.(ABSTRACT TRUNCATED AT 250 WORDS