Pharmacokinetic and pharmacodynamic studies of acute interaction between warfarin enantiomers and chloramphenicol in rats.
The purpose of this investigation was to explore the mechanisms and possible stereoselectivity of the interaction between warfarin and chloramphenicol in rats. Chloramphenicol had no apparent effect on the serum protein binding of R-(+)-warfarin or S-(-)-warfarin in vitro or in vivo. Treatment with i.p. chloramphenicol, 50 mg/kg every 4 hr or 30 mg/kg every 6 hr, decreased the plasma clearance of free warfarin by one-half or more, with no apparent stereoselectivity. The volume of distribution was not significantly affected; the half-life of each warfarin enantiomer was appreciably increased by chloramphenicol. Treatment with chloramphenicol had no apparent effect on relative liver size and on serum aspartate aminotransferase activity. Prothrombin complex activity in plasma was not affected by in vitro addition or in vivo administration of chloramphenicol alone. Chloramphenicol treatment did not affect significantly the elimination kinetics of endogenous prothrombin complex activity and the plasma concentration of free R-(+)-warfarin or S-(-)-warfarin required to decrease prothrombin complex activity synthesis rate to one-half of normal. It appears that the pronounced potentiation of the anticoagulant effect of warfarin by chloramphenicol is due only to inhibition of warfarin metabolism and that this effect is not stereoselective.
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002701:Chloramphenicol / Q000494:pharmacology*; D004347:Drug Interactions; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D011485:Protein Binding; D011516:Prothrombin / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D014859:Warfarin / Q000378:metabolism*
D001798:Blood Proteins; D014859:Warfarin; D002701:Chloramphenicol; D011516:Prothrombin