Warfarin phenylbutazone interaction with

Chierichetti S, Bianchi G, Cerri B. Comparison of feprazone and phenylbutazone interaction with warfarin inman. CurrTherRes ( 915) 18, 568-72. 

The most serious interactions with warfarin are those that increase the anticoagulant effect and the risk of bleeding. The most dangerous of these interactions are the pharmacokinetic interactions with the pyrazolones phenylbutazone and... 

Even more subtle effects arise for drug interactions of a non-chiral drug with a chiral one. Phenylbutazone is not chiral in itself but it can interact with a chiral drug, warfarin, to change the activity of the latter. Phenylbutazone inhibits the oxidative metabolism of the (S)-(-) form of warfarin, (which is five times more potent than the (/ )-(+) form) and thereby decreases its clearance. Conversely, phenylbutazone induces the enzymatic reduction of the (/ ) form thus increasing the clearance.93 Analysis of total warfarin may indicate little departure from normal pharmacokinetics, but the distribution of eutomer and distomer will have changed markedly. 

Apart from being a diffusional barrier, mucin can also interact with drugs to decrease their bioavailability, as has been shown with tetracycline [106], phenylbutazone, and warfarin [107]. On the other hand, studies in rats showed that binding of some water-soluble drugs to intestinal mucus was essential for their absorption and that damage to the mucus significantly reduced absorption [108], The acidic mucus is essential for lipid absorption and could be important for the diffusion of lipophilic drugs (see below). 

The area of clinical pharmacology that first directed attention to the consequences of stereoisomerism on therapeutic and pharmacokinetics was that of drug interactions, particularly those of the anticoagulant warfarin. Not only may drug interactions be stereoselective, but there is a potential for one stereoisomer to alter the pharmacokinetics and pharmacodynamics of the other. A classical example is the interaction with achiral phenylbutazone, which inhibits the metabolism of active 5-warfarin but stimulates the metabolism of the less active R isomer. Other stereoselective drug interactions include the induced elimination of misoni-dazole by phenytoin. Phenytoin enhances the clearance of (4—)-misonidazole by 56%o, which is higher than the increase in clearance of 33%o noted for (—)-misonidazole. 

Lewis RJ, Trager WF, Chan KK, Breckenridge A, Orme M, Roland M, Schary W. Warfarin. Stereochemical aspects of its metabolism and the interaction with phenylbutazone. J Clin Invest 1974 53(6) 1607-17. 

Clinically important, potentially hazardous interactions with amiodarone, amprenavir, anisindione, antacids, anticoagulants, aprepitant, atazanavir, atovaquone, beclomethasone, buprenorphine, corticosteroids, cortisone, cyclosporine, cyproterone, dabigatran, dapsone, darunavir, delavirdine, dexamethasone, dicumarol, digoxin, eszopiclone, flunisolide, fosamprenavir, gadoxetate, gestrinone, halothane, imatinib, isoniazid, itraconazole, ketoconazole, lapatinib, lorcainide, methylprednisolone, midazolam, nelfinavir, nifedipine, oral contraceptives, phenylbutazone, prednisone, protease inhibitors, pyrazinamide, ramelteon, ritonavir, saquinavir, solifenacin, sunitinib, tacrolimus, telithromycin, temsirolimus, tipranavir, tolvaptan, trabectedin, triamcinolone, triazolam, voriconazole, warfarin, zaleplon... 

The interaction with HSA of drugs such as phenylbutazone and its analogues (319), dicoumarol (320), warfarin, 4-hydroxy-coumarin or... 

Five patients stabilised on warfarin had a mean prothrombin time rise from 29 to 38 seconds after taking feprazone 200 mg twice daily for 5 days, despite a 40% reduction in the warfarin dosage (from 5 to 3 mg daily). Four days after feprazone was stopped, their prothrombin times were almost back to usual. The interaction with feprazone was less marked than that with phenylbutazone. ... 

The most important drug interaction caused by displacement from plasma proteins occur with coumarin anticoagulants. Phenylbutazone displaces warfarin from its... 

These studies provide evidence for at least four binding sites in HSA one for tryptophan, that also interacts strongly with many other compounds one that appears to be very specific for bilirubin one high-affinity site for palmitate and one high-affinity site for warfarin, indomethacin, phenylbutazone, and a number of other drugs (i.e. see Ref. 36). Each of these sites appears to be separate and distinct from each of the others. 

M. E. Jones, B. C. Sallustio, Y. Purdie, and E J. Meffin, Enantioselective disposition of 2-arylpropionic acid non-steroidal anti-inflammatory drugs. II. 2-Phenylpropionic acid binding, /. Pharmacol. Exp Ther., 238 288 (1986). R. A. O Reilly, W. E Trager, C. H. Motley, and W. Howald, Stereoselective interaction of phenylbutazone with (12C/13C) warfarin pseudoracemates in man, /. Cfm. Invest., 65 746 (1980). 

O Reilly RA, Goulart DA. Comparative interaction of sulfinpyrazone and phenylbutazone with racemic warfarin alteration in vivo of free fraction of plasma warfarin. J Pharmacol Exp Ther 1981 219(3) 691-4. 

---