Disposition characteristics of coumarin as a function of age in the beagle dog model

Coumarin (C, CAS 91-64-5) is a high extraction ratio drug, and its clearance reflects the liver blood flow. The purpose of this study was to investigate the alterations in the pharmacokinetics of C as a function of age, and to evaluate the suitability of beagle dog model to study age dependent changes in the hepatic function. In this longitudinal study, C was administered intravenously to male beagle dogs, ranging in age from < 1 to 15 years. The total clearance decreased significantly from 30.67 +/- 9.58 to 16.61 +/- 2.35 ml/min/kg and the ratio of AUC of glucuronide metabolite to parent drug decreased from 1.26 +/- 0.52 to 0.72 +/- 0.17 in old dogs. No significant changes were observed in apparent volume of distribution and elimination half-life. The changes in clearance of C parallels the observed reduction in the liver blood flow in man, suggesting that the beagle dog appears to be a good model for drug disposition studies in gerontokinetics.