| Summary: | The Yup'ik Alaska Native people are under‐represented in genetic research, but have unique pharmacogene variation that may critically impact their response to drug therapy. Full gene resequencing of CYP2C9 in the Yup'ik population identified novel, relatively common CYP2C9 variants, including CYP2C9M1L (M1L), a coding region single nucleotide polymorphism hypothesized to confer a poor metabolism activity phenotype by disrupting the start codon. M1L is present at a minor allele frequency of 7.1% in the Yup'ik, placing the population at risk for adverse drug interactions with narrow therapeutic index CYP2C9 substrates such as (S)‐warfarin, phenytoin, and tolbutamide. This study's objective was to characterize the catalytic efficiency of MIL in vivo by evaluating the pharmacokinetic behavior of naproxen, a probe for CYP2C9 activity, in genotyped Yup'ik participants. Targeted genotyping was conducted to identify heterozygous and homozygous M1L individuals from 906 representative members of the Yup'ik population. CYP2C9 mediates the O‐demethylation of naproxen to its 6‐O‐desmethyl metabolite, which is glucuronidated or sulfonated to secondary metabolites, all of which are excreted into the urine. Thus, a change in the urinary metabolite to parent ratio is indicative of a change in CYP2C9 intrinsic formation clearance to 6‐O‐desmethyl naproxen. We developed and validated a novel LC/MS method for simultaneous quantification of (S)‐naproxen, (S)‐6‐O‐desmethyl naproxen, and (S)‐naproxen acyl glucuronide in human urine. Preliminary analysis of one‐half of the final study population revealed an average ratio of 6‐O‐desmethyl naproxen to unchanged naproxen of 18.0 ± 7.7 (n = 7), 10.1 ± 4.5 (n = 7), and 15.6 (n = 2) for the M1L reference, heterozygote, and homozygote variant groups, respectively. ANOVA analysis was borderline significant (p = 0.06) and pairwise comparison of the homozygous reference and heterozygous groups (p = 0.06) suggested reduced activity for the M1L variant. The effect of the novel M1L variant and its ...
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