CO2 breath tests using 14C-caffeine, 14C-methacetin and 14C-phenacetin for assessing postnatal development of monooxygenase activities in rats and marmosets.
The time course in which the activities of cytochrome P450-dependent drug-metabolizing enzymes develop during the perinatal period differs for various types of monooxygenases as well as for various animal species. Using [3-methyl14C]-, [7-methyl14C]-caffeine, [14CH3]-methacetin and [14C2H5]-phenacetin as substrates in breath tests, the developmental changes in the rates of 14CO2 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 14CO2 in the caffeine breath tests on the 1st day of life. This value increased gradually reaching adult rates of 14CO2 exhalation after 21 days for [3-methyl14C]-caffeine and after 25 days for [7-methyl14C]-caffeine. In marmosets the rate of 14CO2 exhalation for [3-methyl14C]- and [7-methyl14C]-caffeine was also low at birth and developed gradually reaching adult values of 14CO2 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 14CO2 reached adult values. Offspring of marmosets reached adult values of 14CO2 exhalation at 8 days postnatally when using [14CO2]-methacetin as substrate and at 30 days postnatally using [14C2H5]-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.
Kinderklinik der Freien Universität Berlin, FRG.
N
N
Krüger
H
H
Helge
D
D
Neubert
D000081:Acetamides / Q000493:pharmacokinetics*; D000367:Age Factors; D000818:Animals; D001944:Breath Tests; D002110:Caffeine / Q000493:pharmacokinetics*; D002144:Callithrix; D002245:Carbon Dioxide / Q000032:analysis*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003640:Dealkylation; D005260:Female; D010615:Phenacetin / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
D000081:Acetamides; C035495:methacetin; D002245:Carbon Dioxide; D002110:Caffeine; D003577:Cytochrome P-450 Enzyme System; D010615:Phenacetin