@article {Henderson345, author = {Lindsay M. Henderson and Scarlett E. Hopkins and Bert B. Boyer and Timothy A. Thornton and Allan E. Rettie and Kenneth E. Thummel}, title = {In Vivo Functional Effects of CYP2C9 M1L, a Novel and Common Variant in the Yup{\textquoteright}ik Alaska Native Population}, volume = {49}, number = {5}, pages = {345--352}, year = {2021}, doi = {10.1124/dmd.120.000301}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Alaska Native people are under-represented in genetic research but have unique gene variation that may critically impact their response to pharmacotherapy. Full resequencing of CYP2C9 in a cross-section of this population identified CYP2C9 Met1Leu (M1L), a novel, relatively common single nucleotide polymorphism hypothesized to confer CYP2C9 poor metabolizer phenotype by disrupting the start codon. M1L is present at a minor allele frequency of 6.3\% in Yup{\textquoteright}ik Alaska Native people and thus can contribute to the risk of an adverse drug response from narrow-therapeutic-index CYP2C9 substrates such as (S)-warfarin. This study{\textquoteright}s objective was to characterize the catalytic efficiency of the Leu1 variant enzyme in vivo by evaluating the pharmacokinetic behavior of naproxen, a probe substrate for CYP2C9 activity, in genotyped Yup{\textquoteright}ik participants. We first confirmed the selectivity of (S)-naproxen O-demethylation by CYP2C9 using activity-phenotyped human liver microsomes and selective cytochrome P450 inhibitors and then developed and validated a novel liquid chromatography mass spectrometry method for simultaneous quantification of (S)-naproxen, (S)-O-desmethylnaproxen, and naproxen acyl glucuronide in human urine. The average ratio of (S)-O-desmethylnaproxen to unchanged (S)-naproxen in urine was 18.0 {\textpm} 8.0 (n = 11) for the homozygous CYP2C9 Met1 reference group and 10.3 {\textpm} 6.6 (n = 11) for the Leu1 variant carrier group (P = 0.011). The effect of M1L variation on CYP2C9 function and its potential to alter the pharmacokinetics of drugs metabolized by the enzyme has clinical implications and should be included in a variant screening panel when pharmacogenetic testing in the Alaska Native population is warranted.Significance Statement The novel CYP2C9 Met1Leu variant in Alaska Native people was recently identified. This study validated (S)-naproxen as a CYP2C9 probe substrate to characterize the in vivo functional activity of the CYP2C9 Leu1 variant. The results of this pharmacogenetic-pharmacokinetic study suggest that the CYP2C9 Leu1 variant exhibits loss of enzyme activity. This finding may be important to consider when administering narrow-therapeutic-index medications metabolized by CYP2C9 and also compels further investigation to characterize novel genetic variation in understudied populations.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/49/5/345}, eprint = {https://dmd.aspetjournals.org/content/49/5/345.full.pdf}, journal = {Drug Metabolism and Disposition} }