What are the medication considerations for a patient who is a poor metabolizer of CYP2B6 (Cytochrome P450 2B6)?

CYP2B6 Poor Metabolizer: Medication Considerations

For patients who are poor metabolizers of CYP2B6, dose reductions are required for efavirenz and cyclophosphamide, while bupropion should be avoided or used with extreme caution due to significantly elevated drug exposure and increased risk of toxicity.

Key Medications Requiring Adjustment

Efavirenz (HIV Treatment)

• Poor metabolizers experience 2.25-fold higher plasma concentrations compared to normal metabolizers, leading to QTc prolongation and increased neuropsychiatric side effects 1
• The standard 600 mg daily dose results in mean QTc prolongation of 8.7 ms (upper bound 11.3 ms) in CYP2B6*6/*6 genotype carriers 1
• Dose reduction should be strongly considered in poor metabolizers to minimize cardiac and CNS toxicity, though specific dosing guidelines are not established 1
• Monitor for increased nervous system symptoms including involuntary muscle contractions 1

Cyclophosphamide (Immunosuppressant/Chemotherapy)

• CYP2B6 is a primary enzyme responsible for bioactivation of cyclophosphamide to its active 4-hydroxycyclophosphamide metabolite 2
• Poor metabolizers may have reduced therapeutic efficacy due to decreased conversion to active metabolites 2
• The CYP2B6*6/*6 genotype paradoxically shows enhanced bioactivation in some studies, creating clinical uncertainty 2
• Close monitoring of therapeutic response and toxicity is essential, as interindividual variability is substantial in cyclophosphamide pharmacokinetics 2

Bupropion (Antidepressant/Smoking Cessation)

• Bupropion is primarily metabolized by CYP2B6 to hydroxybupropion 3, 4
• Poor metabolizers show significantly lower metabolite/drug ratios (mean 0.26 vs 0.59 in rapid metabolizers, p<0.0001) 3
• Approximately 20.56% of North Indian populations are poor metabolizers for CYP2B6 substrates 3
• Risk of seizures and other adverse effects increases with elevated bupropion plasma levels in poor metabolizers 4

Clinical Implications and Monitoring

Genetic Polymorphism Prevalence

• CYP2B6 is one of the most polymorphic CYP genes with over 100 described SNPs 4
• The CYP2B6*6 allele (c.516G>T, Q172H) is the most common variant causing poor metabolism 5
• The mechanism involves aberrant splicing leading to reduced functional mRNA, protein expression, and enzymatic activity 5
• Ethnic variations exist: poor metabolizer phenotypes vary from <1% in Asian populations to up to 10% in Caucasians for CYP2D6 (similar patterns expected for CYP2B6) 6

Additional CYP2B6 Substrates Requiring Caution

• Ketamine: Reduced metabolism may prolong anesthetic effects 4
• Propofol: Altered pharmacokinetics possible in poor metabolizers 4
• Pethidine (Meperidine): Increased parent drug exposure with potential toxicity 4

Common Pitfalls to Avoid

• Do not assume normal dosing is safe without considering metabolizer status for CYP2B6 substrates 1, 4
• Avoid polypharmacy with CYP2B6 inhibitors (such as clopidogrel, ticlopidine) in poor metabolizers, as this compounds the metabolic deficiency 4
• Do not overlook drug-drug interactions: CYP2B6 is susceptible to both induction and inhibition, which can further complicate poor metabolizer phenotypes 4
• Genetic testing may be warranted before initiating therapy with narrow therapeutic index CYP2B6 substrates, particularly efavirenz 1