Evaluation of a [13C]-dextromethorphan breath test to assess CYP2D6 phenotype

A [C-13]-dextrometh orphan ([C-13]-DM) breath test was evaluated to assess its feasibility as a rapid, phenotypingassay for CYP2D6 activity. [C-13]-DM (0.5 mg/kg) was administered orally with water or potassium bicarbonate-sodium bicarbonate to 30 adult Caucasian volunteers (n = 1 each): CYP2D6 poor metabolizers (2 null alleles; PM-0) and extensive metabolizers with 1 (EM-1) or 2 functional alleles (EM2). CYP2D6 phenotype was determined by (CO2)-C-13 enrichment measured by infrared spectrometry (delta-over-baseline [DOB] value) in expired breath samples collected before and up to 240 minutes after [C-13]-DM ingestion and by 4-hour urinary metabolite ratio. The PM-0 group was readily distinguishable from either EM group by both the breath test and urinary metabolite ratio. Using a single point determination of phenotype at 40 minutes and defining PMs as subjects with a DOB 0.5, the sensitivity of the method was 100%; specificity was 95% with 95% accuracy and resulted in the misclassification of 1 EM-1 individual as a PM. Modification of the initial protocol (timing of potassium bicarbonate-sodium bicarbonate administrution relative to dose) yielded comparable results, but there was a tendency toward increased DOB values. Although further development is required, these studies suggest that the [C-13]-DM breath test offers promise as a rapid, minimally invasive phenotyping assay for CYP2D6 activity.