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Optimized LC-MS/MS Method for the High-throughput Analysis of Clinical Samples of Ivacaftor, Its Major Metabolites, and Lumacaftor in Biological Fluids of Cystic Fibrosis Patients
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Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole

H-R He1, J-Y Sun, X-D Ren

  • 1Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China.

European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology
|December 18, 2014
PubMed

Insights

Genetic variations in CYP3A4 influence voriconazole levels. A new single-nucleotide polymorphism (SNP), rs4646437, was linked to higher voriconazole plasma concentrations in patients with invasive fungal infections.

Area of Science:

  • Pharmacogenomics
  • Drug Metabolism
  • Mycology

Background:

  • Voriconazole is a key antifungal agent for invasive fungal infections (IFIs).
  • Its metabolism heavily involves the cytochrome P450 (CYP) enzyme system, particularly CYP3A4, CYP3A5, and CYP2C9.
  • Understanding genetic influences on these enzymes is crucial for optimizing voriconazole therapy.

Purpose of the Study:

  • To investigate the impact of genetic polymorphisms in CYP3A4, CYP3A5, and CYP2C9 on voriconazole plasma concentrations.
  • To identify specific single-nucleotide polymorphisms (SNPs) associated with altered voriconazole pharmacokinetics.

Main Methods:

  • Genotyping of 22 SNPs in CYP3A4, CYP3A5, and CYP2C9 in 158 patients with IFIs.
  • Measurement of voriconazole plasma concentrations using high-performance liquid chromatography (HPLC).
  • Statistical correlation analysis between identified SNPs and voriconazole levels.

Main Results:

  • Voriconazole plasma concentrations varied among patients, with 40 low, 91 normal, and 27 high levels.
  • A significant association was found between the rs4646437 T allele (in CYP3A4) and higher voriconazole plasma concentrations (p=0.033, OR=2.832).

Conclusions:

  • The rs4646437 SNP in CYP3A4 is newly identified as influencing voriconazole metabolism.
  • This finding offers novel insights into how CYP3A4 genetic variations affect voriconazole pharmacokinetics.
  • Pharmacogenetic profiling could aid in personalizing voriconazole dosing for IFIs.

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