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Evaluation of a [¹³C]-Dextromethorphan Breath Test to Assess CYP2D6 Phenotype

From the Section of Developmental Pharmacology and Experimental Therapeutics, Department of Pediatrics, Children's Mercy Hospitals and Clinics, and University of Missouri–Kansas City, Kansas City, Missouri (Dr Leeder, Dr Pearce, Dr Gaedigk); Medical Products Research & Development, Cambridge Isotope Laboratories, Inc, Andover, Massachusetts (Dr Modak); and Physical Sciences, Inc, Andover, Massachusetts (Dr Rosen).

A [¹³C]-dextromethorphan ([¹³C]-DM) breath test was evaluated to assess its feasibility as a rapid, phenotyping assay for CYP2D6 activity. [¹³C]-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 (EM-2). CYP2D6 phenotype was determined by ¹³CO₂ enrichment measured by infrared spectrometry (delta-over-baseline [DOB] value) in expired breath samples collected before and up to 240 minutes after [¹³C]-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 administration 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 [¹³C]-DM breath test offers promise as a rapid, minimally invasive phenotyping assay for CYP2D6 activity.

Key Words: CYP2D6 • phenotype • dextromethorphan • breath test

Address for reprints: J. Steven Leeder, PharmD, PhD, Section of Developmental Pharmacology and Experimental Therapeutics, Children's Mercy Hospitals and Clinics, 2401 Gillham Road, Kansas City, MO 64108; e-mail: sleeder{at}cmh.edu.

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