The in vivo measurement of expired 14CO2 derived from the N-demethylation of aminopyrine as a reflection of the in vitro hepatic cytochrome P-450 drug-metabolism activity in rats.
The kinetics of 14CO2 production in rats were investigated after oral, ip, or iv administration of 14C-aminopyrine (AP) at several dose levels, and after pretreatment with phenobarbital (PB) or partial hepatectomy to produce alterations in hepatic function. Several kinetic parameters were assessed with each route of administration and at each dose level (0.1, 10, and 50 mg/kg). The parameters found most useful were: time to reach peak, peak rate, 14CO2 production per min at 20 or 30 min expressed as percentage of total administered 14C  (R20 or R30), and half-life of the decline in 14CO2 production after peak. It was found that the R30 value after oral administration or R20 after the ip administration of AP (10 mg/kg) reflected alterations in hepatic function without significant overlap of values. The use of the R20 or R30 parameters determined from a single collection was further assessed in control and in PB- and CoCl2-pretreated animals and found to be capable of distinguishing between these different groups of animals. In addition, the AP breath test (ABT) kinetics were not significantly affected by 3-methylcholanthrene pretreatment. In another set of experiments, R30 values determined in controls and in PB- and CoCl2-pretreated rats demonstrated excellent correlation to changes in hepatic microsomal AP and ethylmorphine N-demethylase and aniline hydroxylase activities and cytochrome P-450 content. similar correlations were obtained with R20 after the ip administration of 10 mg of AP per kg. These findings indicate that the ABT is capable of accurately assessing AP N-demethylase activity and other parameters of hepatic mono-oxygenase activity.
D000284:Administration, Oral; D000633:Aminopyrine N-Demethylase / Q000378:metabolism*; D000818:Animals; D001944:Breath Tests / Q000379:methods; D002245:Carbon Dioxide / Q000032:analysis*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D002245:Carbon Dioxide; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D000633:Aminopyrine N-Demethylase; D010634:Phenobarbital