Abstract
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. 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 (80mg/kg), intranasal or intravenous (16.7mg/kg) route. At predefined time points, animals were sacrificed and plasma and tissues were collected to quantify zonisamide and describe its pharmacokinetics. 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. 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.
Highlights
Since the beginning of the XXI century (2000–2005), zonisamide (1,2-benzisoxazole-3-methanesulfonamide) is licensed in the US and European Union for the treatment of generalized and focal seizures, as monotherapy in firstly diagnosed adults and as add-on therapy in adults and children with at least 6 years old [1]
The results found for Alamar Blue assay (Fig. 2) demonstrated no decrease on the viability of the Calu-3 and RPMI-2650 cells in the presence of zonisamide for 24 h at the tested concentrations (1–100 μM), since no statistically significant differences were observed compared to the negative control
Aiming at formulating a successful and original nose-to-brain drug delivery system, but keeping it simple and achievable, the experimental design was optimized in order to warrant that zonisamide was administered in olfactory mucosa of the respiratory mucosa
Summary
Since the beginning of the XXI century (2000–2005), zonisamide (1,2-benzisoxazole-3-methanesulfonamide) is licensed in the US and European Union for the treatment of generalized and focal seizures, as monotherapy in firstly diagnosed adults and as add-on therapy in adults and children with at least 6 years old [1]. Zonisamide demonstrated to improve motor symptoms in patients with Parkinson’s disease when co-administered with levodopa [2,3], being currently approved in Japan as adjunctive therapy of Parkinson’s disease at lower doses than those used in epilepsy [4]. Zonisamide revealed to be effective in relieving chronic and episodic cluster headaches [5]. Underlying this widespread clinical use are probably the multiple mechanisms of action of zonisamide, encompassing the blockage of voltage-dependent sodium channels and T-type calcium channels, which contribute to neural membranes stabilization [6], inhibition of carbonic anhydrase [7], alteration of dopamine metabolism [2] and reduction of glutamate release [8]. Zonisamide improved the treatment of dementia with Lewy bodies parkinsonism when it was added as an adjunct to levodopa [8]
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