4.7 Article

Towards the Elucidation of the Pharmacokinetics of Voriconazole: A Quantitative Characterization of Its Metabolism

Journal

PHARMACEUTICS
Volume 14, Issue 3, Pages -

Publisher

MDPI
DOI: 10.3390/pharmaceutics14030477

Keywords

voriconazole; drug metabolism; pharmacokinetics; CYP P450 enzymes; CYP inhibition; intersystem extrapolation factors; time-dependent inhibition

Funding

  1. AbbVie Deutschland GmbH and Co. KG
  2. AstraZeneca Ltd.
  3. Boehringer Ingelheim Pharma GmbH Co. KG
  4. Grunenthal GmbH
  5. F. Hoffmann-La Roche Ltd.
  6. Merck KGaA
  7. Sanofi
  8. Federal Ministry of Education and Research

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This study quantitatively evaluated the metabolism and inhibition properties of voriconazole, a small-molecule drug with complex metabolism. The findings contribute to the understanding of voriconazole's pharmacokinetics and provide a basis for optimized treatment.
The small-molecule drug voriconazole (VRC) shows a complex and not yet fully understood metabolism. Consequently, its in vivo pharmacokinetics are challenging to predict, leading to therapy failures or adverse events. Thus, a quantitative in vitro characterization of the metabolism and inhibition properties of VRC for human CYP enzymes was aimed for. The Michaelis-Menten kinetics of voriconazole N-oxide (NO) formation, the major circulating metabolite, by CYP2C19, CYP2C9 and CYP3A4, was determined in incubations of human recombinant CYP enzymes and liver and intestine microsomes. The contribution of the individual enzymes to NO formation was 63.1% CYP2C19, 13.4% CYP2C9 and 29.5% CYP3A4 as determined by specific CYP inhibition in microsomes and intersystem extrapolation factors. The type of inhibition and inhibitory potential of VRC, NO and hydroxyvoriconazole (OH-VRC), emerging to be formed independently of CYP enzymes, were evaluated by their effects on CYP marker reactions. Time-independent inhibition by VRC, NO and OH-VRC was observed on all three enzymes with NO being the weakest and VRC and OH-VRC being comparably strong inhibitors of CYP2C9 and CYP3A4. CYP2C19 was significantly inhibited by VRC only. Overall, the quantitative in vitro evaluations of the metabolism contributed to the elucidation of the pharmacokinetics of VRC and provided a basis for physiologically-based pharmacokinetic modeling and thus VRC treatment optimization.

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