Warfarin pharmacokinetic interactions

Vigilance for drug-drug interactions is required because of the greater number of medications prescribed to elderly patients and enhanced sensitivity to adverse effects. Pharmacokinetic interactions include metabolic enzyme induction or inhibition and protein binding displacement interactions (e.g., divalproex and warfarin). Pharmacodynamic interactions include additive sedation and cognitive toxicity, which increases risk of falls and other impairments. 

Pharmacokinetic interactions Preliminary evidence suggests that Saint-John s-wort induces the cytochrome oxidase enzyme isoform CYP3A4 (Ernst 1999). This raises the potential for pharmacokinetic interactions with drugs metabolized by the same enzyme. A few cases have been reported of reduced warfarin levels (Yue et al. 2000). Similar interactions have also been reported for concurrent use with digoxin, theophylline, and cyclosporin (Nebel et al. 1999 Ruschitzka et al. 2000 Johne et al. 1999). As with any other medication, potential interactions should be considered when taking a combination of drugs. 

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... 

Chan E, McLachlan AJ, O Reilly R, et al. Stereochemical aspects of warfarin drug interactions use of a combined pharmacokinetic-pharmacodynamic model. Clin Pharmacol Ther 1994 56 286-294. 

Pharmacokinetic interaction the drugs interact remotely from the target site to alter plasma (and other tissue) concentrations so that the amount of the drug at the target site of clinical effect is altered, e.g. enzyme induction by rifampicin will reduce the plasma concentration of warfarin enzyme inhibition by ciprofloxacin will elevate the concentration of theophylline. 

Vesell, E.S. Passananti, G.T. Johnson, A.Q. Failure of indomethacin and warfarin to interact in normal human volunteers. J. Clin. Pharmacokinet. 1975, 15, 486 95. 

A retrospective analysis of 3995 patients treated with azithromycin did not show any pharmacokinetic interactions in patients who were also taking various other drugs, including warfarin (1,45). 

Avmi WM, Hussein Z, Granneman GR, Patterson KJ, Dube LM, Cavanaugh JH. Pharmacodynamic and stereoselective pharmacokinetic interactions between zUeuton and warfarin in humans. Clin Pharmacokinet 1995 29(Suppl 2) 67-76. 

Azithromycin can increase the effect of warfarin (183), perhaps by inhibiting its metabolism. Despite only modest effects of macrohdes on serum warfarin concentrations and increases in prothrombin time (119), morbidity caused by hemorrhage may be significant, as illustrated by several case reports (184-188). It is hkely that this interaction is potentiated by other factors, such as old age or dietary restrictions (119). However, a retrospective analysis of 3995 patients treated with azithromycin did not show any pharmacokinetic interaction in patients who were also taking warfarin (127). 

Makino, T., Wakushima, H., Okamoto, T., Okukubo, Y., Deguchi, Y., and Kano, Y. 2002. Pharmacokinetic interactions between warfarin and kangen-karyu, a Chinese traditional herbal medicine, and their synergistic action. J. Ethnopharmacol. 82, 35—40. 

Drug Interactions. Levetiracetam neither inhibits nor indnces the CYP450, UGT, or epoxide hydrolase enzyme systems, and in vitro data predict a low potential for pharmacokinetic interactions. Levetiracetam does not appear to interact with other AEDs, warfarin, digoxin, or oral contraceptive drngs. ° ... 

No significant pharmacokinetic interactions between paroxetine and warfarin have been found to date. However, anecdotal reports suggest that bleeding tendency may be increased by the co-administration of the two drugs. Clinically significant bleeding was observed in approximately 25% of healthy volunteers receiving paroxetine 30 mg/day and warfarin 5 mg/day for 14 days. Y ... 

To date, the combined olanzapine-warfarin regimen has not revealed any pharmacokinetic interactions. No interactions have been reported to date between aripiprazole and... 

Slattery J, Yacobi A, Levy G. Comparative pharmacokinetics of coumarin anticoagulants. XXV Warfarin-ibuprofen interaction in rats. J Pharm Sci 1977 66 943-947. 

The minor pharmacokinetic interaction between ciprofloxacin and warfarin in patients taking warfarin would appear to be established, but unlikely to be clinically relevant. Similarly no other quinolone has been shown to have a clinically significant interaction with warfarin. Despite this, there are isolated published case reports of marked over-anticoagulation with many of the quinolones, and other known unpublished cases reported to regulatory authorities. Given the widespread use of warfarin and quinolones, these interactions would appear to be rare. 

The manufacturers of rivastigmine say that no pharmacokinetic interaction has been noted between rivastigmine and warfarin in healthy subjects. In addition, rivastigmine did not affect the increase in prothrombin time seen with warfarin. 

TakahashiH, Kashima T, Kimura S, MurataN, TakabaT, Iwade K, Abe T, Tainaka H, Yas-umori T, Echizen H. Pharmacokinetic interaction between warfarin and a uricosuric agent, bucolome application of in vitro approaches to piedictii in vivo reduction of ( ) warfarin clearance. DmgMetab Dispos (1999) 27, 1179-86. 

In healthy subjects given warfarin until at steady state, felodipine 10 mg daily for 14 days did not alter the dose of warfarin required to maintain a stable INR, or the pharmacokinetics of 5- or R-warfarin. Because felodipine does not interact with warfarin it has been used as a control drug in retrospective cohort studies assessing warfarin drug interactions. ... 

No special precautions would seem to be necessary during the concurrent use of warfarin and dihydropyridine ealeium-channel blockers. Although the minor pharmacokinetic interaction between diltiazem and warfarin would appear to be established, in the studies cited this did not change anticoagulant control, and is therefore unlikely to be of clinical importance. Verapamil would be expected to cause a similar pharmacokinetic interaction, although no data appear to be available on this. 

Not known. Based on in vitro data, both entacapone and tolcapone were thought to potentially interfere with the metabolism of drugs by the cytochrome P450 isoenzyme CYP2C9, such as 5-warfarin. " However, the above study shows that entacapone does not alter 5-warfarin pharmacokinetics, and tolcapone is also thought not expected to interact by this mechanism because it does not interact with tolbutamide , (p.516), another CYP2C9 substrate. 

Zhou H, Patat A, Parks V, Buckwalter M, Met2ger D, Korth-Biadley I Absence of a pharmacokinetic interaction between etanercept and warfarin J Clin Pharmacol (2004) 44, 543-50. 

Nizatidine 300 mg daily for 2 weeks had no significant effect on the prothrombin times, kaolin-cephalin clotting times, the activity of factors II, Vn, XI and X, or on steady-state semm warfarin levels in 7 healthy subjects taking warfarin. A lack of a pharmacokinetic interaction was also reported in the preliminary results of another study. An isolated case of gastrointestinal bleeding, associated with markedly prolonged prothrombin times, occurred after a 78-year-old took six doses of nizatidine 300 mg. ... 

Cimetidine binds with the cytochrome P450 isoenzymes and inhibits oxidative metabolism in the liver. Although cimetidine is considered to be a general inhibitor, it exhibits a degree of specificity for certain isoenzymes such as CYP1A2 and CYP2C19. These isoenzymes are principally involved in the metabolism ofR-warfarin and not S-warfarin (see metabolism of the coumarins , (p.358), for more detail). Thus, the interaction between warfarin and cimetidine has been found to be stereoselective (i.e. cimetidine interacts with theR-isomer but not with theS-isomer). " Because R-warfarin is the less active isomer, and the pharmacokinetic interaction is not marked, the interaction is generally modest. 

Some NSAIDs are inhibitors of the cytochrome P450 isoenzyme CYP2C9, and inhibit the metabolism of warfarin via this isoenzyme. There is also possibly a pharmacokinetic interaction with NSAIDs that are substrates for CYP2C9. People with variant CYP2C9 (about 5 to 11% of Caucasians) have a lower metabolising capacity for warfarin, and require much lower maintenance doses. It is possible that use of an NSAID that is a CYP2C9 substrate may result in reduced warfarin metabolism, although this requires confirmation in controlled studies. 

No pharmacokinetic interaction was observed when vardenafll was given with warfarin, and the prothrombin time was unchanged. ... 

---