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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.

The distribution, elimination, and anticoagulant effect of dicumarol and warfarin were determined in adult males rats following intravenous injection of single doses of these drugs in crossover experiments. The biological half-life of dicumarol ranged from 5 to 28 hr; that of warfarin ranged from 9 to 30 hr. There was a statistically significant correlation between the following pharmacokinetic characteristics of dicumarol and warfarin in individual animals: biological half-life, apparent volume of distribution, total plasma clearance, and concentration in plasma eliciting one-half the maximum anticoagulant effect (effective concentration). The mean ratio of the respective biological half-lives (warfarin/dicumarol) was 1.42, and that of the apparent volumes of distribution was 1.50. The ratio of the effective plasma concentrations (dicumarol/warfarin) was correlated negatively with the half-life of dicumarol and positively with the ratio of the half-life values (warfarin/dicumarol) in individual animals. Additional studies with serum samples from other rats showed pronounced interindividual differences in the serum protein binding of both dicumarol and warfarin and a strong correlation between the protein binding of these two drugs in serum of individual animals. The results of this study, together with the results of previous studies in this series, indicate that serum protein binding is the major determinant of interindividual differences in the pharmacokinetics of dicumarol and warfarin in rats under these experimental conditions.

This investigation was designed to determine if the reported stereoselectivity of the pharmacokinetic interaction between warfarin and metronidazole in humans occurs also in rats and if the potentiation of the anticoagulant effect of warfarin can be ascribed solely to inhibition of warfarin metabolism by metronidazole. Metronidazole had no effect on the serum protein binding of racemic warfarin in vitro over a wide concentration range but decreased the protein binding of R-(+)-warfarin and S-(-)-warfarin in vivo, perhaps indirectly through metabolite(s). Treatment with i.p. metronidazole, 100 mg/kg every 6 hr, decreased the plasma clearance of free warfarin ("intrinsic clearance"). This inhibitory effect was more pronounced with S-(-)-warfarin than with R-(+)-warfarin (congruent to 60 and congruent to 30%, respectively). Metronidazole did not affect plasma prothrombin complex activity in vitro but reduced it in vivo. Metronidazole treatment increased the elimination rate constant for endogenous prothrombin complex activity and decreased the plasma concentration of free R-(+)-warfarin required to decrease prothrombin complex activity synthesis rate to one-half of normal (there were insufficient data to determine the effect of metronidazole on the activity of the other enantiomer). It is concluded that metronidazole preferentially inhibits the metabolism of S-(-)-warfarin in rats as in humans but that (at least in rats) the stereoselectivity is not absolute. Moreover, metronidazole has an indirect inhibitory effect on warfarin protein binding in vivo and also affects the pharmacodynamics of warfarin as well as the blood clotting process per se.