Effect of age on the pharmacokinetics of coumarin

Coumarin was administered i.v. to male beagle dogs, ranging in age from 0.33 to 11.08 years. Some of these dogs were used more than once in the study as their ages progressed. When divided into two groups, young (less than 5 years) and elderly (greater than 5 years), the total plasma clearance decreased significantly as a function of age from 30.67 +/- 9.86 ml/min/kg in the young group (n = 7) to 17.31 +/- 4.35 ml/min/kg in the elderly group (n = 10). No significant changes were found in apparent volume of distribution and elimination half-life. Because coumarin is a drug of high extraction ratio, and liver blood flow decreases with age, the reduction in total clearance is blood flow dependent. 7-Hydroxycoumarin, the major metabolite, did not show any change in elimination half-life as function of age. The ratio of AUC parent drug: metabolite increased about 10-fold as function of age, indicating decreased hydroxylation and glucuronidation.