EFFECT OF AGE ON THEOPHYLLINE PHARMACOKINETICS IN DOGS

Differences between neonatal and adult animals in their response to dr ugs can usually be attributed to altered disposition processes. Effect of age on the pharmacokinetics of theophylline was determined after I V administration of the drug to 10 groups of dogs at 1, 2, 3, 4, 8, 12 , 16, 24, 52, and 104 weeks of age. Plasma theophylline concentration curves for all groups were adjusted to a biexponential kinetic, with r apid initial distribution phase and slower elimination phase. It also was noticed that young dogs have a slower elimination half-life (1 wee k old, t1/2beta = 987 minutes) than do older animals (8 weeks old, t1/ 2beta = 138 minutes). The values then plateaued until 16 weeks of age, increasing slightly at more advanced age (104 weeks old, t1/2beta = 2 82 minutes). A similar pattern was followed with respect to clearance (1-week-old pups, Cl = 1.17 ml/min/kg of body weight), which increased progressively to reach a value of 7.09 ml/min/kg at 16 weeks of age, then decreased to 3.5 ml/min/kg at 104 weeks of age. Volume of distrib ution beta, in relation to body weight, was not significantly differen t between age groups (between 1.2 and 1.6 L/kg; P less-than-or-equal-t o 0.03). Theophylline biotransformation mechanisms may be mainly respo nsible for Cl and t1/2beta variations. This leads us to suggest that q uantitative and qualitative modifications in the P-450 mono-oxygenase system are responsible for the variations observed in pharmacokinetic variables of theophylline between dogs of different ages. These findin gs may have clinical relevance with regard to the therapeutic range of theophylline. For this reason, dosage should be carefully adjusted in younger animals.