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136) 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.
2021 Drug metabolism and disposition: the biological fate of chemicals
* In Vivo Functional Effects of CYP2C9 M1L, a Novel and Common Variant in the Yup'ik Alaska Native Population.
- 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'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'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'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 ± 8.0 (n = 11) for the homozygous CYP2C9Met1 reference group and 10.3 ± 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.
=>1.さらにずっと, さらに先に, 一層遠く, その上, 更に, もっと遠い, なお一層の, さらに遠く,
もっと先に, いっそうはるかに, さらにまた, さらになお(furthermore), 2.進める, 助成する, 促進する
Overview of verb further
The verb further has 2 senses (first 2 from tagged texts)
1. (7) foster, further -- (promote the growth of; "Foster our children's well-being and education")
2. (2) promote, advance, boost, further, encourage -- (contribute to the progress or growth of; "I
am promoting the use of computers in the classroom")
Overview of adj further
The adj further has 1 sense (first 1 from tagged texts)
1. (2) further, farther -- (more distant in especially degree; "nothing could be further from the
truth"; "further from our expectations"; "farther from the truth"; "farther from our expectations")
Overview of adv further
The adv further has 3 senses (first 3 from tagged texts)
1. (33) further, farther -- (to or at a greater extent or degree or a more advanced stage (`further'
is used more often than `farther' in this abstract sense); "further complicated by uncertainty about
the future"; "let's not discuss it further"; "nothing could be further from the truth"; "they are
further along in their research than we expected"; "the application of the law was extended
farther"; "he is going no farther in his studies")
2. (10) further -- (in addition or furthermore; "if we further suppose"; "stated further that he
would not cooperate with them"; "they are definitely coming; further, they should be here already")
3. (1) farther, further -- (to or at a greater distance in time or space (`farther' is used more
frequently than `further' in this physical sense); "farther north"; "moved farther away"; "farther
down the corridor"; "the practice may go back still farther to the Druids"; "went only three miles
further"; "further in the future")
Overview of adv far
The adv far has 5 senses (first 4 from tagged texts)
1. (61) far -- (to a considerable degree; very much; "a far far better thing that I do"; "felt far
worse than yesterday"; "eyes far too close together")
2. (39) far -- (at or to or from a great distance in space; "he traveled far"; "strayed far from
home"; "sat far away from each other")
3. (22) far -- (at or to a certain point or degree; "I can only go so far before I have to give up";
"how far can we get with this kind of argument?")
4. (3) far -- (remote in time; "if we could see far into the future"; "all that happened far in the
past")
5. far -- (to an advanced stage or point; "a young man who will go very far")
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