Drug interactions of amitriptyline and nortriptyline with warfarin in the rat.
Treatment of rats with amitriptyline or nortriptyline for 6 days at 6, 15 and 30 mg/kg produced no increases in the activities of aniline hydroxylase and aminopyrine N-demethylase or the content of microsomal protein and cytochrome P-450. Significant decreases in aminopyrine N-demethylase activity and cytochrome P-450 content were observed at 30 mg/kg. This inhibition of activity appeared to be at the level of cytochrome P-450 and not a cytotoxic effect in liver cells. Concomitant administration of amitriptyline or nortriptyline (6, 15 and 30 mg/kg)with warfarin to rats produced a dose dependent increase in the prothrombin time. At high doses of the tricyclic antidepressants, these increases in prothrombin time correlated with increases observed in the plasma half-life of warfarin. In vitro studies suggested that amitriptyline and nortriptyline inhibited the metabolism of warfarin. A double-reciprocal plot (Lineweaver-Burk method) showed this inhibition to be competitive. Nortriptyline produced greater inhibition of warfarin metabolism than amitriptyline and correspondingly greater enhancement of the anticoagulant effect.
D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D004347:Drug Interactions; D006207:Half-Life; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009661:Nortriptyline / Q000494:pharmacology*; D011517:Prothrombin Time; D051381:Rats; D014859:Warfarin / Q000097:blood / Q000494:pharmacology*
D000639:Amitriptyline; D014859:Warfarin; D009661:Nortriptyline; D006899:Mixed Function Oxygenases