Pharmacokinetics and metabolism of darifenacin in the mouse, rat, dog and man.
1. Following intravenous administration to animals at 2.5 mg/kg, darifenacin exhibited 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. Darifenacin was metabolized by three main routes in all species: monohydroxylation, oxidative dihydrobenzfuran ring opening and N-dealkylation. There were no marked species differences in the metabolism of darifenacin.
Beaumont
K C
KC
Department of Drug Metabolism, Pfizer Central Research, Sandwich, UK.
Cussans
N J
NJ
Nichols
D J
DJ
Smith
D A
DA
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000818:Animals; D019540:Area Under Curve; D001572:Benzofurans / Q000737:chemistry / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D004285:Dogs; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008875:Middle Aged; D011759:Pyrrolidines / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D015203:Reproducibility of Results; D013045:Species Specificity
D001572:Benzofurans; D002250:Carbon Radioisotopes; D011759:Pyrrolidines; C101207:darifenacin