Effect of age on theophylline pharmacokinetics in dogs

Jordi Alberola From the Divisió de Farmacologia, Unitat de Farmacologia i Toxicologia, Facultat de Veterinària, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.

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Yolanda Pérez From the Divisió de Farmacologia, Unitat de Farmacologia i Toxicologia, Facultat de Veterinària, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.

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Ana Puigdemont From the Divisió de Farmacologia, Unitat de Farmacologia i Toxicologia, Facultat de Veterinària, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.

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Margarita Arboix From the Divisió de Farmacologia, Unitat de Farmacologia i Toxicologia, Facultat de Veterinària, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.

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Summary

Differences between neonatal and adult animals in their response to drugs can usually be attributed to altered disposition processes. Effect of age on the pharmacokinetics of theophylline was determined after IV 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 rapid initial distribution phase and slower elimination phase. It also was noticed that young dogs have a slower elimination half-life (1 week old, t1/2β = 987 minutes) than do older animals (8 weeks old, t1/2β = 138 minutes). The values then plateaued until 16 weeks of age, increasing slightly at more advanced age (104 weeks old, t1/2β = 282 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 distribution β, in relation to body weight, was not significantly different between age groups (between 1.2 and 1.6 L/kg; P ≤ 0.03).

Theophylline biotransformation mechanisms may be mainly responsible for Cl and t1/2β variations. This leads us to suggest that quantitative 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 findings may have clinical relevance with regard to the therapeutic range of theophylline. For this reason, dosage should be carefully adjusted in younger animals.

Summary

Differences between neonatal and adult animals in their response to drugs can usually be attributed to altered disposition processes. Effect of age on the pharmacokinetics of theophylline was determined after IV 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 rapid initial distribution phase and slower elimination phase. It also was noticed that young dogs have a slower elimination half-life (1 week old, t1/2β = 987 minutes) than do older animals (8 weeks old, t1/2β = 138 minutes). The values then plateaued until 16 weeks of age, increasing slightly at more advanced age (104 weeks old, t1/2β = 282 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 distribution β, in relation to body weight, was not significantly different between age groups (between 1.2 and 1.6 L/kg; P ≤ 0.03).

Theophylline biotransformation mechanisms may be mainly responsible for Cl and t1/2β variations. This leads us to suggest that quantitative 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 findings may have clinical relevance with regard to the therapeutic range of theophylline. For this reason, dosage should be carefully adjusted in younger animals.

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