CO(2) Breath Tests Using 14C-Caffeine, 14C-Methacetin and 14C-Phenacetin for Assessing Postnatal Development of Monooxygenase Activities in Rats and Marmosets

Abstract

The time course in which the activities of cytochrome P(450)-dependent drugmetabolizing enzymes develop during the perinatal period differs for various types of monooxygenases as well as for various animal species. Using [3-methyl^14C]-, [7-methyl^14C]-caffeine, [14CH(3)]-methacetin and [14C(2)H(5)]-phenacetin as substrates in breath tests, the developmental changes in the rates of 14CO(2) formation, due to changes in the activity of monooxygenases, were studied in rats and marmoset monkeys (Callithrix jacchus). In rats a rate of 0.006% of the dose administered/min was found to be exhaled as 14CO(2) in the caffeine breath tests on the 1st day of life. This value increased gradually reaching adult rates of 14CO(2) exhalation after 21 days for [3-methyl^14C]-caffeine and after 25 days for [7-methyl^14C]-caffeine. In marmosets the rate of 14CO(2) exhalation for [3-methyl^14C]- and [7-methyl^14C]- caffeine was also low at birth and developed gradually reaching adult values of 14CO(2) exhalation within 120-200 days. In rats the capacity for dealkylation of methacetin and phenacetin developed much faster compared with caffeine: 9 days postnatally, the exhalation of 14CO(2) reached adult values. Offspring of marmosets reached adult values of 14C02 exhalation at 8 days postnatally when using [14CO(2)]-methacetin as substrate and at 30 days postnatally using [14C(2)H(5)]-phenacetin in the breath test. The results suggest that the monooxygenases for the N-demethylation of caffeine, the O-demethylation of methacetin and the O-deethylation are rather substrate specific in the two species studied. The breath tests used are sensitive methods for assessing the development of different monooxygenases in vivo in rats and marmosets, and they may well (using 13C-labelled substrates) be applicable for studies in children to monitor effects of certain environmental pollutants.

Alteration in the tissue retention of [14C]‐caffeine in pregnant mice by dimethylsulfoxide

“…Our study did not attempt to separate radioactivity in maternal and fetal tissues into that from the parent compound and from the metabolites. Kruger et al [1991] re- ported that up to 15% of 14C-labeled 3-or 7-methylxanthine given to rodents can be demethylated and exhaled as 14C-CO, in 180 min, suggesting the likelihood that demethylation at I-methyl position in mice followed by exhalation of C-CO, could account for at least some of the 5 to 10% loss of radioactivity in our study. Caffeine is eliminated rapidly from adult humans and animals by hepatic metabolism with an average half life of 4 hr [Rall, 19901.…”