Effect of grapefruit juice on serum voriconazole concentrations in the mouse

Sugar, Alan M.; Liu, X. P.

doi:10.1080/mmy.38.3.209.212

Cited by 72 publications

(40 citation statements)

References 14 publications

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“…In the present study, mRNA levels of genes for other CYP forms, including Cyp2b10, Cyp2c29, Cyp2c37, and Cyp2c55, were increased by VRC treatment in wild-type mice, raising the possibility that these enzymes are partially involved in the autoinduc- (25)(26)(27)(28)(29)(30). Because furanocoumarin derivatives in grapefruit juice are known to inhibit CYP3A activities (31,32), these facts corroborate the idea that CYP3A is mainly involved in VRC metabolism in mouse livers.…”

Section: Discussionsupporting

confidence: 75%

Coordinated Roles of Pregnane X Receptor and Constitutive Androstane Receptor in Autoinduction of Voriconazole Metabolism in Mice

Ohbuchi

Yoshinari

Kaneko

et al. 2013

Antimicrob Agents Chemother

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The antifungal efficacy of voriconazole (VRC) differs among host species, with potent efficacy in humans but less in rodents. We investigated the possible involvement of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in the speciesspecific efficacy of VRC through pharmacokinetic analyses using genetically modified mice and primary human hepatocytes. VRC (30 mg/kg) was orally administered to wild-type, Pxr-null, Car-null, and Pxr-and Car-null (Pxr/Car-null) mice for 7 days. Hepatic VRC metabolism was significantly increased by VRC administration, and the elimination rates of plasma VRC were much higher on day 7 than on day 1 in wild-type mice. This autoinduction was also observed in Pxr-null and Car-null mice but not in Pxr/Car-null mice, suggesting coordinated roles of PXR and CAR in the autoinduction of VRC metabolism in mice. Hepatic Cyp3a11 mRNA levels were increased by VRC administration, hepatic metabolic activities for VRC were correlated with CYP3A activities, and the induced VRC metabolism was inhibited by ketoconazole (a CYP3A inhibitor). In primary human hepatocytes, VRC barely increased mRNA levels of CYP3A4 and CYP2B6 (human PXR/CAR target genes) at its therapeutic concentrations. In conclusion, these results suggest that VRC is metabolized mainly by CYP3A11 in mouse livers and that PXR-and CAR-mediated CYP3A11 induction, namely, autoinduction of VRC metabolism, is a primary reason for the ineffectiveness of VRC in mice. A limited ability of VRC to activate human PXR/CAR at its clinical concentration might explain the VRC efficacy in humans. Therefore, the ability to activate PXR/CAR might determine the VRC efficacy in different mammalian species.

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Section: Discussionsupporting

confidence: 75%

Coordinated Roles of Pregnane X Receptor and Constitutive Androstane Receptor in Autoinduction of Voriconazole Metabolism in Mice

Ohbuchi

Yoshinari

Kaneko

et al. 2013

Antimicrob Agents Chemother

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“…This can be attributable to the inherent problems of testing VRC in the murine model where VRC levels in the serum decay rapidly even when administering grapefruit juice to the animals, which has been shown to increase the serum amounts of this drug up to therapeutic levels. 56 Accordingly, in an alternative mammalian model, the guinea pig, VRC performed better against T. asahii infections even at a lower dose. 57 In contrast, both VRC and FLC improved the G. mellonella survival infected with all 3 Trichosporon species.…”

Section: Discussionmentioning

confidence: 99%

The development of animal infection models and antifungal efficacy assays against clinical isolates ofTrichosporon asahii,T. asteroidesandT. inkin

et al. 2015

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The present study developed Galleria mellonella and murine infection models for the study of Trichosporon infections. The utility of the developed animal models was demonstrated through the assessment of virulence and antifungal efficacy for 7 clinical isolates of Trichosporon asahii, T. asteroides and T. inkin. The susceptibility of the Trichosporon isolates to several common antifungal drugs was tested in vitro using the broth microdilution and the Etest methods. The E-test method depicted a lower minimal inhibitory concentration (MIC) for amphotericin and a slightly higher MIC for caspofungin, while MICs observed for the azoles were different but comparable between both methods. All three Trichosporon species established infection in both the G. mellonella and immunosuppressed murine models. Species and strain dependent differences were observed in both the G. mellonella and murine models. T. asahii was demonstrated to be more virulent than the other 2 species in both animal hosts. Significant differences in virulence were observed between strains for T. asteroides in the murine model. In both animal models, fluconazole and voriconazole were able to improve the survival of the animals compared to the untreated control groups infected with any of the 3 Trichosporon species. In G. mellonella, amphotericin was not able to reduce mortality in any of the 3 species. In contrast, amphotericin was able to reduce murine mortality in the T. asahii or T. inkin models, respectively. Hence, the developed animal infection models can be directly applicable to the future deeper investigation of the molecular determinants of Trichosporon virulence and antifungal resistance.

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“…We therefore sought a design that involved minimizing the possible therapeutic effects of each drug alone, in an effort to demonstrate enhanced effects of the combination. The guinea pig is the preferred animal for experiments with voriconazole because the drug is rapidly eliminated in mice (24). We used real-time PCR, since it is superior to culture for accurate measurement of tissue burdens of A. fumigatus (3).…”

mentioning

confidence: 99%

Efficacy of Caspofungin and Voriconazole Combinations in Experimental Aspergillosis

MacCallum

Whyte

Odds

2005

Antimicrob Agents Chemother

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Guinea pigs were infected with Aspergillus fumigatus at two challenge doses and treated for 7 days with a placebo, intraperitoneal caspofungin (1 mg/kg daily), oral voriconazole (1 mg/kg twice a day), or a combination of the caspofungin and voriconazole treatments. The combination therapy statistically significantly prolonged survival over that with the control at both challenge doses and achieved a statistically significant reduction in kidney burdens as measured by quantitative PCR. The same was true for animals given caspofungin alone at both levels of challenge and for animals treated with voriconazole alone at the lower challenge dose. However, the effects of combination therapy on prolongation of survival were greater than those of either monotherapy at both challenge doses, and the reduction in kidney burdens with combination therapy was significantly greater than that with caspofungin alone in the animals given the lower challenge dose. No synergistic interactive effects were seen for the two agents in checkerboard titration experiments in vitro. We conclude that therapy of experimental aspergillosis with caspofungin and voriconazole combined offers slight additional improvements in efficacy rather than effects of a clearly synergistic nature.

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Effect of grapefruit juice on serum voriconazole concentrations in the mouse

Cited by 72 publications

References 14 publications

Coordinated Roles of Pregnane X Receptor and Constitutive Androstane Receptor in Autoinduction of Voriconazole Metabolism in Mice

Coordinated Roles of Pregnane X Receptor and Constitutive Androstane Receptor in Autoinduction of Voriconazole Metabolism in Mice

The development of animal infection models and antifungal efficacy assays against clinical isolates ofTrichosporon asahii,T. asteroidesandT. inkin

Efficacy of Caspofungin and Voriconazole Combinations in Experimental Aspergillosis

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