Pharmacokinetic profile of theophylline in isolated perfused liver of rabbits at different ages. Development of drug-metabolizing activity during ontogenesis.

The ontogeny of the biotransformation of exogenous and endogenous compounds has been mostly studied using liver cells and microsomal fractions. We have used liver perfusion for the first time to characterize the development of the total P-450 cytochrome-dependent system in the rabbit, with theophylline (TH) as tool substance. Livers of 0- to 60-day-old rabbits were perfused with TH (10 micrograms/ml) for 3 hr. Metabolizing enzymes (cytochrome P-450), ATP, glutathione, and glycogen were measured in liver tissue after perfusion. Lactate dehydrogenase, glutamic-oxalacetic transaminase, glucose, and urea were assayed in the medium throughout perfusion. The pharmacokinetic profile of TH was determined. The activity of total cytochrome P-450, as well as the intrinsic unbound clearance and TH metabolites production, increased following a similar sigmoidal pattern and reached a plateau around 30-45 days of the postnatal development of rabbit liver. The perfused tissue showed no signs of age-related hepatic damage or toxic effects of TH. Thus, the results in perfused liver predict its metabolic capacity during ontogenesis.