A 62-year-old diabetic on simvastatin is prescribed clarithromycin for an exacerbation of bronchiectasis. Three days later he reports severe muscle pain with a creatine kinase of 12,000 U/L. The most likely mechanism is:

• A Clarithromycin-induced myocyte apoptosis independent of statin levels
• B Potent CYP3A4 inhibition causing markedly elevated plasma simvastatin concentrations ✓
• C Inhibition of intestinal P-glycoprotein reducing statin biliary excretion
• D Additive mitochondrial toxicity of both drugs on skeletal muscle

Explanation

Simvastatin and lovastatin are extensively metabolized by CYP3A4. Clarithromycin and erythromycin are strong CYP3A4 inhibitors, raising statin exposure many-fold and causing rhabdomyolysis. Azithromycin lacks significant CYP3A4 inhibition and is the safer macrolide in such patients. P-glycoprotein modulation contributes to digoxin interactions rather than this presentation, and the mechanism is pharmacokinetic, not additive mitochondrial injury.

Reference: Katzung's Basic and Clinical Pharmacology, 15th ed.

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