The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human.

doi:10.1124/DMD.31.6.731

Paper

The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human.

Published Jun 1, 2003 · S. Roffey, S. Cole, P. Comby

Drug metabolism and disposition: the biological fate of chemicals

Q1 SJR score

309

Citations

23

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Abstract

Voriconazole is a new triazole antifungal agent with potent, wide-spectrum activity. Its pharmacokinetics and metabolism have been studied in mouse, rat, rabbit, dog, guinea pig, and humans after single and multiple administration by both oral and intravenous routes. Absorption of voriconazole is essentially complete in all species. The elimination of voriconazole is characterized by non-linear pharmacokinetics in all species. Consequently, pharmacokinetic parameters are dependent upon dose, and a superproportional increase in area under the curve is seen with increasing dose in rat and dog toxicology studies. Following multiple administration, there is a decrease in systemic exposure. This is most pronounced in mouse and rat, less so in dog, and not observed in guinea pig or rabbit. Repeat-dose toxicology studies in mouse, rat, and dog have demonstrated that induction of cytochrome P450 by voriconazole (autoinduction of metabolism) is responsible for the decreased exposure in these species. Autoinduction of metabolism is not observed in humans, and plasma steady-state concentrations remain constant with time. Voriconazole is extensively metabolized in all species. The major pathways in humans involve fluoropyrimidine N-oxidation, fluoropyrimidine hydroxylation, and methyl hydroxylation. Also, N-oxidation facilitates cleavage of the molecule, resulting in loss of the fluoropyrimidine moiety and subsequent conjugation with glucuronic acid. Major pathways are represented in animal species. The major circulating metabolite in rat, dog, and human is the N-oxide of voriconazole. It is not thought to contribute to efficacy since it is at least 100-fold less potent than voriconazole against fungal pathogens in vitro.

Non-RCT

Animal Study

Highly Cited

Study Snapshot

Voriconazole is a potent antifungal agent with non-linear pharmacokinetics and extensive metabolism in all species, with autoinduction of metabolism in some species.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human.

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References

Pharmacokinetics and Safety of Voriconazole following Intravenous- to Oral-Dose Escalation Regimens

Voriconazole shows nonlinear pharmacokinetics, with maximum concentrations occurring at the end of intravenous infusion and between 1.4 and 1.8 hours after oral administration.

Induction and drug development.

Drug development should focus on ensuring moderate daily dose size, increasing potency against the target, and optimizing pharmacokinetics, rather than inducing enzymes.

Efficacy of voriconazole against invasive pulmonary aspergillosis in a guinea-pig model.

Voriconazole shows a trend towards better survival and decreased fungal burden in the lungs, making it an attractive alternative to potentially toxic amphotericin B for treating invasive pulmonary aspergillosis.

A new triazole, voriconazole (UK-109,496), blocks sterol biosynthesis in Candida albicans and Candida krusei

Voriconazole effectively inhibits sterol biosynthesis in both fluconazole-susceptible and fluconazole-resistant Candida albicans strains, potentially enhancing its antifungal activity.

Activity of voriconazole (UK-109,496) against clinical isolates of Aspergillus species and its effectiveness in an experimental model of invasive pulmonary aspergillosis

Voriconazole effectively inhibits Aspergillus spp. growth in vitro and delays or prevents mortality in an experimental model of invasive pulmonary aspergillosis.

Citations

Therapeutic drug monitoring of azole antifungal agents.

Therapeutic drug monitoring (TDM) is crucial for assessing pharmacokinetic parameters, preventing drug-drug interactions, adverse events, and fungal resistance in azole antifungal agents.

A Physiologically Based Pharmacokinetic Model of Voriconazole in Human CNS -- Integrating Time-Dependent Inhibition of CYP3A4, Genetic Polymorphisms of CYP2C19 and Possible Transporter Mechanisms.

The PBPK model effectively simulates voriconazole distribution in the human CNS, providing guidance for clinical individualized treatment and improving treatment effects and prognosis in CNS infection patients.

Renal Replacement Therapy as a New Indicator of Voriconazole Clearance in a Population Pharmacokinetic Analysis of Critically Ill Patients

qCRP, CRRT, CLCR, PLT, and PT affect voriconazole clearance in critically ill patients, with 200 mg q12h being sufficient for most common pathogens and requiring higher doses for MIC 2 mg/L.

Ciprofloxacin enhances therapeutic levels of voriconazole through CYP450 inhibition in the common raven (Corvus corax), possibly improving efficacy against aspergillosis: a pilot study.

Ciprofloxacin combined with voriconazole effectively maintains therapeutic levels in common ravens, potentially improving their treatment of chronic aspergillosis.

Mass spectrometric methods for evaluation of voriconazole avian pharmacokinetics and the inhibition of its cytochrome P450-induced metabolism

Ravens can rapidly metabolize voriconazole, making it difficult to maintain therapeutic levels without CYP inhibitors, but ciprofloxacin is effective.

Invasive fungal infections and oomycoses in cats 2. Antifungal therapy

Antifungal drugs effectively treat invasive fungal infections and oomycoses in cats, but long treatment times and potential relapses require careful monitoring and management.

Electrochemical Simulation of Phase I Hepatic Metabolism of Voriconazole Using a Screen-Printed Iron(II) Phthalocyanine Electrode

The iron(II) phthalocyanine electrode is an efficient and cost-effective tool for simulating hepatic voriconazole metabolism, offering new possibilities in pharmaceutical research.