Astemizole and Terfenadine have been withdrawn due to intrinsic cardiotoxicity. The interaction risk with grapefruit juice or erythromycin is explained by which mechanism?

• A. Displacement from the protein binding of Astemizole or Terfenadine by Grapefruit juice or Erythromycin
• B. Decreased urinary excretion of Astemizole and Terfenadine since Grapefruit juice and Erythromycin competes with them in using transporters
• C. Inhibition of the CYP3A4 enzyme by Grapefruit juice or Erythromycin
• D. Increased absorption of Astemizole and Terfenadine due to the effects of Grapefruit juice and Erythromycin on the GI tract

Answer: (C)

The interaction is driven by inhibition of the CYP3A4 enzyme, which slows metabolism of astemizole and terfenadine. Grapefruit juice and erythromycin inhibit intestinal CYP3A4, leading to higher plasma levels of these drugs. Elevated concentrations increase the risk of QT prolongation and torsades de pointes, which is why these agents were withdrawn for their cardiotoxic potential. Other ideas like displacement from protein binding, competition for renal transporters, or increased absorption don’t account for the major rise in drug exposure and associated cardiac risk; the key is reduced metabolism via CYP3A4 inhibition.