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The novel carboxylesterase 1 variant c.662A>G may decrease the bioactivation of oseltamivir in humans.

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The CES1 c.662A>G gene variant may reduce its enzyme activity, impacting oseltamivir pharmacokinetics. This study found altered oseltamivir exposure in carriers, suggesting potential clinical relevance for influenza treatment.

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Area of Science:

  • Pharmacogenomics
  • Drug Metabolism
  • Enzyme Kinetics

Background:

  • Human carboxylesterase 1 (CES1) is crucial for metabolizing drugs like oseltamivir.
  • A novel CES1 c.662A>G single nucleotide polymorphism (SNP) was computationally predicted to reduce CES1 activity.
  • This study investigated the real-world impact of the c.662A>G SNP on oseltamivir pharmacokinetics.

Purpose of the Study:

  • To evaluate the effect of the CES1 c.662A>G SNP on oseltamivir pharmacokinetics in healthy human subjects.
  • To determine if the c.662A>G genotype influences the metabolism and exposure of oseltamivir and its active metabolite.

Main Methods:

  • Twenty healthy subjects received a single 75 mg oral dose of oseltamivir.
  • Subjects were genotyped for the CES1 c.662A>G SNP (8 heterozygous, 12 non-carriers).
  • Plasma and urine concentrations of oseltamivir and oseltamivir carboxylate were quantified using LC-MS/MS.

Main Results:

  • Increased oseltamivir systemic exposure (AUC0-48h) by 10% in c.662AG carriers.
  • Reduced oseltamivir carboxylate exposure (AUC0-48h) by 5% in c.662AG carriers.
  • Increased urinary excretion of unchanged oseltamivir by 15% in c.662AG carriers.

Conclusions:

  • The CES1 c.662A>G SNP is associated with altered oseltamivir pharmacokinetics, suggesting reduced CES1 enzymatic activity in heterozygous carriers.
  • Further research is needed to clarify the clinical implications of this genetic variation for CES1 substrate drugs.