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Pre-Clinical Assessment of the Nose-to-Brain Delivery of Zonisamide After Intranasal Administration

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Abstract

Purpose

Zonisamide clinical indications are expanding beyond the classic treatment of epileptic seizures to Parkinson’s disease and other neurodegenerative diseases. However, the systemic safety profile of zonisamide may compromise its use as a first-line drug in any clinical condition. Since zonisamide is marketed as oral formulations, the present study aimed at exploring the potential of the intranasal route to centrally administer zonisamide, evaluating the systemic bioavailability of zonisamide and comparing its brain, lung and kidney pharmacokinetics after intranasal, oral and intravenous administrations.

Methods

In vitro cell studies demonstrated that zonisamide and proposed thermoreversible gels did not affect the viability of RPMI 2650 or Calu-3 cells. Thereafter, male CD-1 mice were randomly administered with zonisamide by oral (80 mg/kg), intranasal or intravenous (16.7 mg/kg) route. At predefined time points, animals were sacrificed and plasma and tissues were collected to quantify zonisamide and describe its pharmacokinetics.

Results

Intranasal route revealed a low absolute bioavailability (54.95%) but the highest value of the ratio between the area under the curve (AUC) between brain and plasma, suggesting lower systemic adverse events and non-inferior effects in central nervous system comparatively to intravenous and oral routes. Furthermore, drug targeting efficiency and direct transport percentage into the brain were 149.54% and 33.13%, respectively, corroborating that a significant fraction of zonisamide suffers direct nose-to-brain transport. Lung and kidney exposures obtained after intranasal administration were lower than those observed after intravenous injection.

Conclusions

This pre-clinical investigation demonstrates a direct nose-to-brain delivery of zonisamide, which may be a promising strategy for the treatment of central diseases.

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Abbreviations

AUC:

Area under drug concentration-time curve

AUCt :

Area under drug concentration-time curve from time zero to the time of last measurable concentration

AUCextrap :

Extrapolated area under drug concentration-time curve

AUCinf :

area under drug concentration-time curve from time zero to infinity

BBB:

Blood-brain barrier

BbrainIN/IV :

Brain bioavailability between IN and IV routes

Cmax :

Maximum concentration

CNS:

Central nervous system

CYP:

Cytochrome P450

CV:

Coefficient of variation

DRE:

Drug-resistant epilepsy

DTE:

Drug targeting efficiency

DTP:

Direct transport percentage

FAbs :

Absolute bioavailability

FRel :

Relative bioavailability

HPLC:

High performance liquid chromatography

IN:

Intranasal

IV:

Intravenous

LLOQ:

Lower limit of quantification

SD:

Standard deviation

SEM:

Standard error of the mean

SMPA:

Sulfamoylacetylphenol glucuronide

tmax :

Time to reach the maximum concentration

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors acknowledge to Fundo Europeu de Desenvolvimento Regional (FEDER) funds through Portugal 2020 in the scope of the Operational Programme for Competitiveness and Internationalisation, and Fundação para a Ciência e Tecnologia (FCT) I.P./MCTES, Portuguese Agency for Scientific Research, through national funds (PIDDAC) within the scope of the research project CENTRO-01-0145-FEDER-03075 and POCI-01-0145-FEDER-030478.

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Authors and Affiliations

  1. Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal

    Joana Gonçalves, Andreia Carona, Joana Bicker, Amílcar Falcão & Ana Fortuna

  2. CIBIT/ICNAS - Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal

    Joana Gonçalves, Andreia Carona, Joana Bicker, Amílcar Falcão & Ana Fortuna

  3. CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal

    Gilberto Alves

  4. Laboratory of Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

    Carla Vitorino

  5. Coimbra Chemistry Center, Department of Chemistry, University of Coimbra, Coimbra, Portugal

    Carla Vitorino

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  1. Joana Gonçalves
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  2. Gilberto Alves
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  3. Andreia Carona
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  4. Joana Bicker
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  7. Ana Fortuna
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Correspondence to Ana Fortuna.

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Gonçalves, J., Alves, G., Carona, A. et al. Pre-Clinical Assessment of the Nose-to-Brain Delivery of Zonisamide After Intranasal Administration. Pharm Res 37, 74 (2020). https://doi.org/10.1007/s11095-020-02786-z

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  • DOI: https://doi.org/10.1007/s11095-020-02786-z

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