Warfarin interaction with macrolides

C. Delavirdine Drug interactions are a major problem with delavirdine, which is metabolized by both CYP3A4 and CYP2D6. Its blood levels are decreased by antacids, ddl. phenytoin. rifampin, and nelfinavir. Conversely, the blood levels of delavirdine are increased by azole anti-fiingals and macrolide antibiotics. Delavirdine increases plasma levels of several benzodiazepines, nifedipine, protea.se inhibitors, quinidine, and warfarin. Delavirdine causes skin rash in up to 20% of patients, and the drug should be avoided in pregnancy since it is teratogenic in animals. 

Erythromycin is a known inhibitor of the cytochrome P450 isoenzyme CYP3A4. However, this isoenzyme has only a minor role in the metabolism of warfarin , (p.358), specifically the less active R-isomer of warfarin. Consequently, only minor increases in the levels of warfarin have been seen in pharmacokinetic studies, which would generally not be expected to be clinically relevant. However, it is possible that even these small changes might be important in a very few patients, particularly those with a low prothrombin complex aetivity. Other macrolides (azithromycin, clarithromycin, dirithromycin, roxithromycin) have less effect on CYP3A4 than erythromycin, and consequently would be expected to have even less effect on the pharmacokinetics of warfarin or acenocoumarol, which is borne out in the few studies available. Nevertheless, cases of interactions have been reported for nearly all these macrolides. Moreover, one cohort study found that clarithromycin increased the risk of an interaction and erythromycin did not. It is possible that there is some other, as yet unidentified, mechanism involved. Alternatively, it is equally possible that the relatively few cases just represent idiosyncratic effects attributable to other factors, and not to any interaction (see also Coumarins -i- Antibacterials , p.365). 

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