Stereoselective interaction of sulfinpyrazone with racemic warfarin and its separated enantiomorphs in man.

Abstract

SUMMARY Although serious hemorrhage during therapeutic coadministration of sulfinpyrazone and racemic warfarin occurs, no prospective studies have been done. In this study, single oral doses of racemic warfarin, 1.5 mg/kg, were administered to six normal subjects with and without oral sulfinpyrazone, 400 mg daily. Both the hypoprothrombinemia (p < 0.001) and the plasma warfarin concentrations (p < 0.05) were significantly augmented. To determine if this interaction was stereoselective, the experiments were repeated in the same subjects with R-and S-warfarin enantiomorphs. S-warfarin with sulfinpyrazone caused a highly significant augmentation of both the hypoprothrombinemia (p < 0.001) and the plasma warfarin concentrations (p < 0.001). R-warfarin with sulfinpyrazone did not significantly change the hypoprothrombinemia but significantly (p < 0.05) reduced warfarin concentrations. Thus, sulfinpyrazone augmented the hypoprothrombinemia of racemic warfarin stereoselectively by reduced metabolic clearance of S-warfarin. Sulfinpyrazone and racemic warfarin are most dangerous when either drug is added to a stabilized regimen of the other drug.SULFINPYRAZONE-INDUCED augmentation of the anticoagulant effect of racemic sodium warfarin was first observed in a patient in 1978.1 Since then, three other patients have been reported in whom the addition of sulfinpyrazone to their long-term regimen of racemic warfarin markedly potentiated the hypoprothrombinemia within 7-10 days.2' 3 Furthermore, seven patients on long-term therapy with sulfinpyrazone who each received only a single 10-15-mg dose of racemic warfarin also had an exaggerated anticoagulant effect, including severe gastrointestinal bleeding in one.4 The mechanism of the interaction was said to be displacement of albumin-bound warfarin by the sulfinpyrazone,1 s but no studies on the plasma concentrations of warfarin or displacement studies with specimens of patient blood were performed.4 To verify the interaction prospectively and to study its mechanism, the effect of sulfinpyrazone on the hypoprothrombinemia and plasma levels of racemic warfarin was studied in six normal subjects. Because this study showed marked potentiation of the anticoagulant effect of the racemate, the experiments were repeated in the same subjects with the separated enantiomorphs of racemic warfarin to determine if the interaction was stereoselective. The results of these experiments suggest a stereoselective mechanism for the interaction of sulfinpyrazone with racemic warfarin. Methods SubjectsSix men, 21-30 years old, were studied. All were paid volunteers who were carefully informed of the nature of the experiments and had signed written consents in accordance with all conditions required by federal regulation and the institutional review board. All were in excellent health and had not taken any other drug during the preceding 2 months. Each subject served as his own control, and the order of the experiments with warfarin alone and with warfarin combined with sulfinpyrazone in the crossove...

Stereoselective interaction between the R enantiomer of warfarin and cimetidine.

“…The increase in AUC and plasma half-life and the decrease in plasma clearance indicate that there is inhibition of metabolism of the R enantiomer but no consistent change in the metabolism of S warfarin. In contrast, previous studies on the stereoselective nature of warfarin drug interactions O'Reilly, 1976O'Reilly, , 1980O'Reilly, , 1982 have shown an increase in the mean plasma half-life of S warfarin due to decreased clearance. The mean plasma half-life of the R enantiomer however has been shown to decrease (phenylbutazone and sulphinpyrazone) or remain unchanged (metronidazole and cotrimoxazole).…”

“…(,ug ml' h) (h) (ml h-' kg') (1 kg') (,sg ml' h) (h) (ml h-' kg-') (I kg-') The results show a stereoselective pharmacokinetic interaction between cimetidine and the R enantiomer of warfarin. R warfarin is less potent than S warfarin O'Reilly, 1974;Wingard et al, 1978 O'Reilly, 1976O'Reilly, , 1980O'Reilly, , 1982 have shown an increase in the mean plasma half-life of S warfarin due to decreased clearance. The mean plasma half-life of the R enantiomer however has been shown to decrease (phenylbutazone and sulphinpyrazone) or remain unchanged (metronidazole and cotrimoxazole).…”

“…metronidazole (O'Reilly, 1976); cotrimoxazole (O'Reilly, 1980); phenylbutazone ; and sulphinpyrazone (O'Reilly, 1982). In each case the inhibition of metabolism has been predominantly that of the S enantiomer.…”

The Effect of Bucolome, a CYP2C9 Inhibitor, on the Pharmacokinetics of Losartan

“…It is a CYP2C9 inhibitor, equipotent to phenylbutazone and sulfinpyrazone. [5][6][7] Therefore, it is suggested that when LOS and CYP2C9 inhibitors are given concomitantly, the bioavailability of E3174 is decreased; leading theoretically to decreases the pharmacodynamic effects of LOS. In this study, to evaluate the potential drug interaction between LOS and CYP2C9 inhibitors, the effects of BUC on the pharmacokinetics of LOS and E3174 were studied in healthy human volunteers and rats.…”

Effect of Induction and Inhibition of Drug Metabolism on Pharmacokinetics and Anticoagulant Activity of the Enantiomers of Phenprocoumon in Rats

“…Moreover, for warfarin it was shown in man that other drugs can affect the metabolism of the enantiomers in a qualitative and quanti-tative different manner. Such stereoselective biotransformation interactions with the warfa rin enantiomers have been demonstrated, e.g., for phenylbutazone (Lewis et ai, 1974), metro nidazole (O'Reilly, 1976), and co-trimoxazole (O'Reilly, 1977) but not for phénobarbital (Breckenridge and Orme, 1976). These findings lead to the suggestion that interactions of cer tain drugs with warfarin could be minimized by treating patients with one of the enantiomers instead of racemic drug (O ' Reilly, 1976;.…”