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CYP2D6 Poor Metabolizer Status Can Be Ruled Out by a Single Genotyping Assay for the -1584G Promoter Polymorphism

¹ Division of Developmental Pharmacology and Medical Toxicology, The Children’s Mercy Hospital and Clinics, Kansas City, MO 64108

² Department of Psychiatry and Medicine, Morehouse School of Medicine, Atlanta, GA 30310

^aaddress correspondence to this author at: The Children’s Mercy Hospital, Division of Clinical Pharmacology, 2401 Gillham Rd., Kansas City, MO 64108; fax 816-855-1958, e-mail agaedigk@cmh.edu

The first 300 words of the full text of this article appear below.

Accurate prediction of CYP2D6 phenotype from genotype data is important for many clinically relevant drugs. Genotyping strategies targeting allelic variants with diminished or no activity to identify poor metabolizers generally works well in Caucasian (1)(2)(3) and Asian (4)(5) populations, but we have had more limited success (i.e., poor concordance) in African Americans, even after extensive testing (6). For example, genotype analysis predicted poor metabolizer status (by Caucasian-derived antimode definition) in only 4 of 14 individuals, and many individuals predicted to be extensive metabolizers presented as "intermediate" metabolizers (6). A single-nucleotide polymorphism in the CYP2D6 promoter region (-1584G) has been reported to confer higher CYP2D6 activity in vivo than -1584C (7), possibly as a consequence of higher expression of CYP2D6 protein (8). This polymorphism was first associated with CYP2D6*2 alleles, and the CYP nomenclature committee subsequently assigned *2[-1584G] as CYP2D6*2A (and noting that -1584G is probably found on all CYP2D6*2 alleles) and *2[-1584C] as CYP2D6*41, respectively (9). However, -1584G also appears to be linked with the functional CYP2D6*35 allele, which has been found in many duplication-negative "ultrarapid" metabolizers (10). For simplicity, we refer to the *2[-1584G] allele cumulatively as CYP2D6*2 because our genotyping procedure does not differentiate among variants CYP2D6*2A through K. For reference, -1584G corresponds to -1496G in Ref. (7).

The goals of this investigation were (a) to explore whether -1584G is exclusively linked to functional allelic variants and hence would allow rapid "positive" identification of extensive metabolizers and reliably rule out poor metabolizer status, and (b) to reevaluate the genotype-to-phenotype correlation data in our . . . [Full Text of this Article]

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