UGT2B15 Poor Metabolism: Medication Management Recommendations
Primary Clinical Consideration
**Individuals with UGT2B15 poor metabolism (homozygous for the 2/2 genotype or D85Y polymorphism) require dose reduction of benzodiazepines metabolized by this enzyme, particularly lorazepam and S-oxazepam, due to significantly reduced clearance and increased drug exposure. 1, 2
Affected Medications and Dosing Adjustments
Benzodiazepines Requiring Dose Modification
Lorazepam: UGT2B15*2/*2 individuals show 0.58-fold lower systemic clearance (42% reduction) compared to *1/*1 genotype, resulting in prolonged drug exposure and enhanced pharmacodynamic effects 1
S-Oxazepam: Exclusively metabolized by UGT2B15, with the *2 allele showing 5-fold lower glucuronidation activity compared to the *1 allele; poor metabolizers require substantial dose reduction 2
Practical dosing approach: Start with 50% of standard doses for lorazepam and oxazepam in UGT2B15*2/*2 individuals, titrate slowly based on clinical response, and monitor closely for excessive sedation 1, 2
Drug-Drug Interactions Requiring Special Attention
Valproate co-administration: Causes 20% additional reduction in lorazepam clearance beyond genetic effects; avoid combination in poor metabolizers or reduce lorazepam dose by 70% if combination is necessary 1
Rifampin co-administration: Increases lorazepam clearance by 140%, but absolute clearance values remain lower in *2/*2 individuals; dose adjustments should account for both genetic status and induction effects 1
Clinical Monitoring Strategy
Pharmacodynamic Assessment
Monitor for enhanced sedation, prolonged psychomotor impairment, and increased visual analog scale scores indicating excessive drug effects in poor metabolizers 1
Assess psychomotor coordination more frequently during initial dosing and after any dose adjustments 1
Timing Considerations
- Peak effects occur earlier and persist longer in UGT2B15 poor metabolizers; extend monitoring periods beyond standard 12-hour assessments 1
Alternative Therapeutic Options
Preferred Benzodiazepines for Poor Metabolizers
R-oxazepam: Metabolized by UGT1A9 and UGT2B7 rather than UGT2B15, making it unaffected by UGT2B15 polymorphism 2
Consider benzodiazepines metabolized by CYP450 enzymes rather than UGT2B15 when genetic testing reveals poor metabolizer status 3
Important Clinical Caveats
The UGT2B15 polymorphism does not affect all substrates equally; while benzodiazepines show marked effects, other substrates like eugenol, naringenin, and 4-methylumbelliferone also demonstrate reduced metabolism 2
Phenotypic prediction accuracy depends on comprehensive genotyping and consideration of concurrent medications that may inhibit or induce UGT2B15 activity 1
Do not provide patient-specific dosing recommendations in pharmacogenomic test reports; instead, provide generalized statements about alternative therapy considerations and list resources like FDA tables for actionable decisions 4