How do anti-epileptic drugs (AEDs) affect biotin levels?

Impact of Anti-Epileptic Drugs on Biotin Levels

Anti-epileptic drugs (AEDs), particularly enzyme-inducing AEDs like phenytoin, carbamazepine, phenobarbital, and primidone, significantly reduce biotin levels in patients, which can lead to clinical manifestations of biotin deficiency and potentially affect treatment outcomes.

Mechanism of AED-Induced Biotin Deficiency

AEDs affect biotin status through several mechanisms:

1. Enzyme induction effects:

   • Older AEDs (carbamazepine, phenytoin, phenobarbital, primidone) induce hepatic cytochrome P450 enzymes 1
   • This accelerates biotin catabolism, leading to increased excretion of biotin metabolites 2

2. Metabolic alterations:

   • AEDs may impair liver mitochondrial function, resulting in reduced biotinidase activity 3
   • Increased urinary excretion of biotin metabolites (bisnorbiotin, biotin sulfoxide) 2

3. Differential effects by AED type:

   • Enzyme-inducing AEDs: Cause significant biotin depletion
   • Valproate: Less impact on biotin levels compared to enzyme-inducing AEDs 4

Clinical Evidence of AED-Induced Biotin Deficiency

Laboratory Findings

• Plasma biotin levels:

  • 74% of epileptics on long-term AED therapy have biotin levels ≤250 ng/L 4
  • Significantly lower plasma biotin in patients on AEDs compared to controls 5

• Biochemical markers:

  • Increased urinary excretion of organic acids associated with biotin-dependent carboxylase deficiency 6:
    • 3-hydroxyisovaleric acid
    • 3-hydroxypropionate
    • Methylcitrate
    • 3-methylcrotonate

• Biotinidase activity:

  • Significantly reduced in patients on higher doses of valproic acid 3
  • Strong inverse correlation between biotinidase activity and VPA blood levels 3

Clinical Manifestations

Biotin deficiency can manifest as:

• Dermatologic issues (seborrheic rash, dermatitis)
• Alopecia (hair loss)
• Neurological symptoms
• Metabolic disturbances

Differences Among AEDs

1. Enzyme-inducing AEDs (phenytoin, carbamazepine, phenobarbital, primidone):

   • Cause most significant reduction in biotin levels 5, 4
   • Associated with increased urinary excretion of organic acids 6
   • Patients with partial epilepsy (who often receive higher doses of these AEDs) show lower biotin levels 5

2. Valproate:

   • Maintains higher biotin levels compared to enzyme-inducing AEDs 4
   • However, high-dose valproate can significantly reduce biotinidase activity 3
   • Different mechanism of action on biotin metabolism compared to enzyme-inducing AEDs

3. Dose-dependent effects:

   • Higher AED doses correlate with lower biotin levels 5
   • Biotinidase activity inversely correlates with valproate blood levels 3

Clinical Implications and Management

Monitoring

• Consider biotin status assessment in patients on long-term AED therapy, particularly those on enzyme-inducing AEDs
• Monitoring is especially important in patients showing:
  • Dermatological manifestations
  • Hair loss
  • Unexplained neurological symptoms

Supplementation

• Biotin supplementation (10 mg/day) has been shown to improve skin lesions and alopecia in patients on valproate 3
• Consider biotin supplementation in patients with:
  • Documented low biotin levels
  • Clinical manifestations of biotin deficiency
  • Long-term use of enzyme-inducing AEDs

AED Selection Considerations

• In patients at high risk for nutritional deficiencies, valproate may have advantages over enzyme-inducing AEDs regarding biotin status 4
• Newer AEDs (levetiracetam, lamotrigine, pregabalin) are preferred over first-generation AEDs due to fewer metabolic interactions 1

Special Considerations

Drug Interactions

• First-generation AEDs (phenytoin, carbamazepine, phenobarbital) are strong inducers of hepatic metabolism and may interfere with many medications 1
• This metabolic induction likely contributes to biotin depletion

Nutritional Requirements

• The ESPEN micronutrient guideline recommends:
  • At least 30 μg of biotin per day in enteral nutrition 1
  • 60 μg biotin per day in parenteral nutrition 1
  • These requirements may be higher in patients on AEDs

Conclusion

Anti-epileptic drugs, particularly enzyme-inducing AEDs, significantly reduce biotin levels through accelerated catabolism and altered metabolism. This can lead to clinical manifestations of biotin deficiency and potentially impact treatment outcomes. Monitoring biotin status and considering supplementation in patients on long-term AED therapy may be beneficial, especially for those showing clinical signs of deficiency.