Pharmacokinetics and metabolism of darifenacin in the mouse, rat, dog and man

Abstract

1. Followingintravenousadministrationto animals at 2 5 mg kg, darifenacinexhibited terminal plasma half-lifes < 2 h due to high plasma clearance (with respect to blood flow) and volumes of distribution greater than total body water.

2. Following oral administration to animals at doses > 4 mg kg there was evidence of saturation of clearance since oral AUCs exceeded those expected from the high plasma clearances. In addition, terminal plasma half-lifes were greater than those estimated from intravenous administration.

3. In man, oral clearance was high with respect to liver blood flow.

4. Following oral administration of the radiolabelled drug to animals and man, unchanged darifenacin was only a minor component of the faecal radioactivity indicating that darifenacin was well absorbed from the gut.

5. Darifenacinwas metabolizedby three main routes in all species: monohydroxylati on, oxidative dihydrobenzfura n ring opening and N–dealkylation. There were no marked species differences in the metabolism of darifenacin.