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

Josefine Schulz,Gerd Mikus,Antonia Thomas,Ayatallah Saleh,Robin Michelet,Charlotte Kloft

doi:10.3390/pharmaceutics14030477

Josefine Schulz, Gerd Mikus + Show 4 more

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https://doi.org/10.3390/pharmaceutics14030477

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Abstract

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.

Highlights

Besides the precise description of the Michaelis-Menten kinetics of VRC Noxidation in human liver microsomes (HLM), recombinant human cytochrome P450 enzymes (rhCYP) and human intestine microsomes (HIM), enzyme contributions were assessed by different approaches highlighting the relevance of the chosen experimental settings
The N-oxidation of VRC was demonstrated in all enzymatic systems investigated, HLM, rhCYP2C19, rhCYP2C9, rhCYP3A4 and HIM, and followed nonlinear Michaelis–Menten kinetics
We demonstrated a relevant inhibitory effect of NO on CYP3A4 and, to a lesser extent, CYP2C9, but only a minor one on CYP2C19, which is in line with Giri et al (IC50 values of 11.2 and 8.7 μM on CYP2C9 and CYP3A4, respectively) [84]

Summary

Introduction

The small-molecule drug voriconazole (VRC, Figure 1), a broad-spectrum, triazole antifungal agent inhibiting the ergosterol biosynthesis of the fungal cell wall [1], is listed by the World Health Organization as an essential medicine for adults and children [2,3]. VRC is used worldwide in first-line therapy of invasive fungal infections such as aspergillosis. Fusarium sp., as well as prophylaxis in patients with haematopoietic stem-cell transplantation [4]. The prevalence of these infections has increased in recent years concurrently with the expanding susceptible patient population, e.g., patients receiving immunosuppressants [5,6,7]. VRC has been marketed since 2002 in the European

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