Which of the following pairs of medications will lead to interactions and toxicity: St John's wort (Hypericum perforatum) & cyclosporine, or simvastatin (Zocor) & erythromycin?

Drug Interactions Leading to Toxicity: St John's Wort & Cyclosporine vs. Simvastatin & Erythromycin

Both St John's wort & cyclosporine and simvastatin & erythromycin pairs will lead to clinically significant drug interactions and toxicity, but the St John's wort & cyclosporine interaction can result in organ rejection and is potentially life-threatening.

St John's Wort & Cyclosporine Interaction

Mechanism of Interaction

• St John's wort is a potent inducer of CYP3A4 and P-glycoprotein (P-gp) 1, 2
• Cyclosporine is extensively metabolized by CYP3A4 and is a substrate of P-gp 3
• This interaction results in significantly decreased cyclosporine blood concentrations

Clinical Consequences

• Markedly reduced cyclosporine blood levels (approximately 50% decrease in dose-normalized concentrations) 4
• Increased risk of transplant rejection due to subtherapeutic immunosuppressant levels 4, 5
• Multiple case reports and clinical trials have documented organ rejection in transplant patients 2
• FDA labeling specifically warns against this combination 3

Simvastatin & Erythromycin Interaction

Mechanism of Interaction

• Erythromycin is a strong CYP3A4 inhibitor 6
• Simvastatin is a substrate of CYP3A4 7
• This interaction results in increased simvastatin blood concentrations

Clinical Consequences

• Increased risk of myopathy and rhabdomyolysis 6
• FDA labeling specifically contraindicates this combination 7
• The American Heart Association recommends avoiding this combination 8
• Can lead to muscle pain, weakness, and potential kidney damage

Comparative Severity

While both drug pairs cause significant interactions:

1. St John's wort & cyclosporine:

   • Results in decreased drug effect (cyclosporine)
   • Can lead to organ rejection in transplant patients
   • Often unexpected as patients may not report herbal supplement use
   • Potentially life-threatening consequences

2. Simvastatin & erythromycin:

   • Results in increased drug effect (simvastatin)
   • Causes predictable toxicity (myopathy/rhabdomyolysis)
   • More likely to be recognized by healthcare providers
   • Toxicity develops gradually and can be monitored

Clinical Management

For St John's wort & cyclosporine:

• Completely avoid concomitant use 3
• If a patient on cyclosporine has been taking St John's wort:
  • Immediately discontinue St John's wort
  • Monitor cyclosporine levels closely
  • Adjust cyclosporine dose as needed
  • Monitor for signs of organ rejection

For simvastatin & erythromycin:

• Contraindicated combination 7
• If erythromycin is required:
  • Temporarily suspend simvastatin during erythromycin treatment
  • Consider alternative antibiotics when possible
  • Monitor for muscle symptoms if co-administration cannot be avoided

Alternative Therapies

Instead of St John's wort with cyclosporine:

• Use conventional antidepressants with less interaction potential
• Consider psychiatric consultation for depression management in transplant patients

Instead of simvastatin with erythromycin:

• Use pravastatin, fluvastatin, or rosuvastatin which have less interaction with erythromycin
• Consider azithromycin as an alternative macrolide with less CYP3A4 inhibition

Key Points to Remember

• Both combinations are dangerous and should be avoided
• The St John's wort & cyclosporine interaction may be more insidious as patients often don't report herbal supplement use
• Always obtain a complete medication history including over-the-counter products and herbal supplements
• The simvastatin & erythromycin interaction is well-recognized and alternative options are readily available