A kinetic evaluation of14CO2 in expired air after14C-methacetin administration in rats, used for thein vivo study of the metabolism of drugs

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Abstract
The pharmacokinetics of the blood level and the patterns ofl4CO2 exhalation were determined simultaneously following i.v. administration of14C-methacetin to the conscious rat. The pattern of exhalation ofl4CO2 did not parallel the biexponential decline of radioactivity in the blood and a delay of 30–40 min preceeded the maximal rate ofl4CO2 exhalation. The total radioactivity exhaled remained constant at 56±4.5% (SD) of the applied dose throughout a tenfold dose range of methacetin (0.6, 4.0 and 6.0 mg/kg i.p.), administered to groups of three rats each and measured over a period of 4 hours. The pattern of radiolabel exhalation was biexponential with the low dose, linear with the medium dose and convex with the high dose. Although the total fraction of the label expired after 4 hours remained constant, the rates of exhalation at the higher dosages exhibited saturation type kinetics. At the higher dosage, since the pattern of14CO2 exhalation did not accurately reflect the decline of methacetin seen in blood, one of the steps occuring between the demethylation process and the production of expired CO2 appears to be rate limiting. Significant increases in the amount ofl4CO2 exhaled within 1 hour were obtained by pretreatment with phenobarbital, rifampicin and 3-methylcholanthrene. Again the proportion of radiolabel expired in 4 hours remained constant. Acute hepatic injury produced by pretreatment with graded doses of carbon tetrachloride resulted in graded reductions in the amount of14CO2 exhaled in the first hour, although the total amount exhaled during the 4 hour collection period did not change. This resulted from a reduction in the maximal exhalation rate and a prolongation of the overall elimination process. It is concluded that the determination of the maximal exhalation rate and of cumulative exhalation within one hour provides useful measures ofl4C-methacetin demethylation capacity. This is also true for conditions of extensive liver damage where terminal exhalation rates cannot easily be determined.