Pharmacokinetics/pharmacodynamic correlations of fluconazole in murine model of cryptococcosis

Santos, Julliana Ribeiro Alves; César, Isabela Costa; Costa, Marliete Carvalho; Ribeiro, Noelly Queiroz; Holanda, Rodrigo Assunção; Ramos, Lais Hott; Freitas, Gustavo José Cota de; Paixão, Tatiane Alves da; Pianetti, Gérson Antônio; Santos, Danielle Anjos dos

doi:10.1016/j.ejps.2016.05.022

Cited by 8 publications

(5 citation statements)

References 28 publications

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“…Similar to previous reports in mice (Humphrey et al, 1985;Santos et al, 2016) and rats (Uchida et al, 2014;Wang et al, 2017;Yang et al, 1996), we show here that fluconazole rapidly modifies the pharmacokinetic profile of (R,S)-ketamine in mice by increasing total brain exposure of (R,S)-ketamine and (R,S)-norketamine. Concomitantly, fluconazole robustly reduced (2S,6S;2R,6R)-HNK (6-HNK) levels.…”

Section: Introductionsupporting

confidence: 92%

Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions

Nguyen,

Guilloux,

Defaix

et al. 2024

Preprint

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ABSTRACT(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine’s metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses. We assessed whether pre-treatment with fluconazole (10 and 20 mg/kg, i.p.) 1 hour prior to ketamine or HNKs (10 mg/kg, i.p.) administration would alter behavioral and neurochemical actions of the drugs in male BALB/cJ mice with a highly anxious phenotype. Extracellular microdialysate levels of glutamate and GABA (Gluext, GABAext) were also measured in the medial prefrontal cortex (mPFC). Pre-treatment with fluconazole altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R,S)-norketamine, while robustly reducing those of (6)-HNKs. At 24 hours post-injection (t24h), fluconazole prevented the sustained AD-like response of ketamine responses in the forced swim test and splash test, as well as the enhanced cortical GABA levels produced by ketamine. A single (2R,6R)-HNK administration selectively rescued the antidepressant-like activity of ketamine in mice pretreated with fluconazole within 24 hours of treatment. Overall, these findings are consistent with an essential role of (6)-HNK in mediating the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients.

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Section: Introductionsupporting

confidence: 92%

Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions

Nguyen,

Guilloux,

Defaix

et al. 2024

Preprint

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“…13,24 In animal models using rabbits, mice and horses, the concentration achieved in the CSF ranged from 41% to 86% of the concentration measured in serum; however, brain concentrations ranged from 10% to 50% of the serum concentration. [58][59][60][66][67][68][69][70][71] In human CSF, a similar range was found (52% to 85% of the serum concentration), but a huge difference was found in brain concentrations of FCZ, which varied from 47% to 116% of the serum concentration. 24 It is important to highlight that only one study analysing FCZ in human brain tissue was found in the literature from 1990…”

Section: Tri a Zo Le Ssupporting

confidence: 57%

“…FCZ is broadly distributed to all organs and tissues, including the CNS, and achieves the highest concentrations in the CSF, even in the absence of meningeal inflammation 13,24 . In animal models using rabbits, mice and horses, the concentration achieved in the CSF ranged from 41% to 86% of the concentration measured in serum; however, brain concentrations ranged from 10% to 50% of the serum concentration 58‐60,66‐71 . In human CSF, a similar range was found (52% to 85% of the serum concentration), but a huge difference was found in brain concentrations of FCZ, which varied from 47% to 116% of the serum concentration 24 .…”

Section: Triazolesmentioning

confidence: 85%

Antifungal drugs: An updated review of central nervous system pharmacokinetics

Wirth

Ishida

2020

Mycoses

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Invasive fungal infections (IFIs) in the central nervous system (CNS) are particularly hard to treat and are associated with high morbidity and mortality rates. Four chemical classes of systemic antifungal agents are used for the treatment of IFIs (eg meningitis), including polyenes, triazoles, pyrimidine analogues and echinocandins. This review will address all of these classes and discuss their penetration and accumulation in the CNS. Treatment of fungal meningitis is based on the antifungal that shows good penetration and accumulation in the CNS. Pharmacokinetic data concerning the entry of antifungal agents into the intracranial compartments are faulty. This review will provide an overview of the ability of systemic antifungals to penetrate the CNS, based on previously published drug physicochemical properties and pharmacokinetic data, for evaluation of the most promising antifungal drugs for the treatment of fungal CNS infections. The studies selected and discussed in this review are from 1990 to 2019.

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“…The recommended dose of fluconazole for cryptococcosis is 400 mg/day, which corresponds to 75 mg/kg in mice in terms of the AUC. 17,18 However, fluconazole at a dose of 320 mg/kg did not exhibit any therapeutic effect in a progressed murine infection model.…”

Section: Discussionmentioning

confidence: 97%

In vitro and in vivo antifungal activities of T-2307, a novel arylamidine, against Cryptococcus gattii: an emerging fungal pathogen

Nishikawa

Fukuda

Mitsuyama

et al. 2017

Journal of Antimicrobial Chemotherapy

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Pharmacokinetics/pharmacodynamic correlations of fluconazole in murine model of cryptococcosis

Cited by 8 publications

References 28 publications

Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions

Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions

Antifungal drugs: An updated review of central nervous system pharmacokinetics

In vitro and in vivo antifungal activities of T-2307, a novel arylamidine, against Cryptococcus gattii: an emerging fungal pathogen

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