Reevaluation of formulas for predicting creatinine clearance in adults and children, using compensated creatinine methods.

ously (7 ), and confirmed the proposed CYP2D6*35 haplotype (10 ). Phenotype-genotype correlation analysis subsequently showed that poor metabolizer status could effectively be ruled out by positive identification of a single functional 1584G-containing allelic variant in 43% of Caucasians but only 12% of African Americans. The 1584G assay can be performed directly on genomic DNA or on a long CYP2D6-specific PCR product encompassing upstream and coding regions of the CYP2D6 gene. The assay is useful for rapid and cost-effective identification of individuals with functional CYP2D6 activity and confirmation of an extensive metabolizer assignment when incorporated in a more intensive genotyping strategy. Although perfect linkage of 1584G to functional alleles was demonstrated in our population samples, it remains to be validated in populations of other ethnic backgrounds. The significantly lower frequency of 1584G in African Americans compared with Caucasians further supports previous findings that CYP2D6 genotyping in African Americans presents unique challenges (6 ). The increased frequency of specific reduced-function and rare nonfunctional alleles (CYP2D6*17, *29, *40, and *42), and the potential existence of additional such alleles because of the residual genotype-phenotype discordance observed by us and others (6, 11, 12), make accurate prediction of phenotype from genotype data difficult in this heterogeneous population. Therefore, exclusion of poor metabolizer status through identification of 1584G carriers offers one solution to this problem. Overrepresentation of CYP2D6*35 among duplicationnegative ultrarapid metabolizers may be attributable to 1584G and increased gene transcription rather than the Val11Met substitution (31G3A) (10 ), which had no effect on activity in vitro (13 ). Although DM phenotype does not appear to differentiate gene duplication-carrying ultrarapid metabolizers from other groups, a correlation between CYP2D6*35 and rapid metabolism (DM/DX 0.003) was evident (data not shown), further supporting the association of the 1584G polymorphism with more rapid metabolism. In conclusion, the 1584C3G polymorphism rules out poor metabolizer status, identifies additional important ethnic differences, and therefore is a valuable addition to CYP2D6 genotyping strategies applied to Caucasian and African-American populations.