A 40-year-old male is well controlled on warfarin for a factor V Leiden deficiency and recurrent deep vein thrombosis. He presents today with a community-acquired pneumonia and is placed on erythromycin. Three days later, he develops bleeding and his INR is 8.0 (indicating an increased time for blood clotting to occur, where INR is international normalized ratio). Which of the following best explains why this bleeding occurred?
Warfarin is metabolized by a specific subset of induced P450 isozymes. The P450 system is used by cells to modify the xenobiotic (in this case the warfarin) such that it can be more easily excreted. Erythromycin, along with other macrolide antibiotics, inhibits the P450 oxidizing system, which in this case would lead to a higher blood level of warfarin and, therefore, the balance of clotting and bleeding is shifted toward excessive bleeding. A stimulation of P450 production by erythromycin would lead to a lower level of warfarin (because of increased metabolism and loss of warfarin by P450) and the potential for excessive clotting. This effect of P450 is a common drug-drug interaction. The causative agents of community- acquired pneumonia do not affect vitamin K absorption in the small intestine, or distribution throughout the body. Erythromycin does not affect mitochondrial transcription, although it may affect mitochondrial translation. Inhibition of mitochondrial protein synthesis, however, will not alter the inhibition of cytochrome P450 activity, and the increased levels of warfarin present, which may lead to increased bleeding.
The erythromycin inhibited cytochrome P450
The erythromycin stimulated cytochrome P450
The causative agent of the pneumonia inhibited vitamin K utilization
The causative agent of the pneumonia stimulated vitamin K utilization
Molecular Genetics