Programa de Pós-Graduação em Farmácia, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil.
Programa de Pós-Graduação em Química, Centro de Ciências Físicas e Matemáticas, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil.
Int J Pharm. 2020 Nov 30;590:119924. doi: 10.1016/j.ijpharm.2020.119924. Epub 2020 Oct 11.
In isolated isoniazid (INH)-resistant strains, deletion or mutations in thekatGgene have been identified, which result in loss of catalase-peroxidase activity. This enzyme plays a key role in the activation of this prodrug. As an alternative, the coordination of the INH to metal complexes has been purposed to activate it regardless of enzyme functionality. Although pentacyanido(isoniazid)ferrate(II) complexes have shown to be effective against resistant strains of Mycobacterium tuberculosis, low oral bioavailability was found. In this context, buccal mucosa was selected as an alternative route to the metal complex delivery. Moreover, oral manifestations of tuberculosis(TB) have been observed in some patients, particularly when resistant strains are present, and no therapeutic options are currently available on the market. Pentacyanidoferrate (PCF-INH) and Prussian-blue (PB-INH) complexes were initially prepared and characterized, followed by buccal permeability studies in Franz-type diffusion cells. The electrochemical potential of the complexes demonstrated their ability to self-activate. Job's method suggested the presence of structural defects in PB-INH complexes, which was correlated with permeability results. In fact, PB-INH showed a higher dissociation rate in salt-rich aqueous medium and thus a high transport rate of INH through the buccal mucosa. Its passage through the tissue would not be possible due to the high molecular size. PCF-INH, in turn, presented a lower dissociation rate in the salt-rich aqueous medium, justifying its slower transport rate through the tissue. Taken together, these results suggest that INH-based metal complexes may be efficiently administered through the buccal route, impacting on both oral bioavailability and microbial resistance.
在分离的异烟肼（INH）耐药株中，已发现 katG 基因缺失或突变，导致过氧化氢酶-过氧化物酶活性丧失。这种酶在该前药的激活中起着关键作用。作为替代方案，已经提出将 INH 配位到金属配合物中，以激活它，而不管酶的功能如何。尽管五氰基（异烟肼）铁（II）配合物已被证明对结核分枝杆菌耐药株有效，但发现其口服生物利用度较低。在这种情况下，颊黏膜被选为金属配合物递送的替代途径。此外，一些患者观察到肺结核（TB）的口腔表现，特别是当存在耐药株时，目前市场上没有可供选择的治疗方法。最初制备和表征了五氰基铁（PCF-INH）和普鲁士蓝（PB-INH）配合物，然后在 Franz 型扩散细胞中进行颊黏膜渗透性研究。配合物的电化学势表明它们能够自我激活。Job 法表明 PB-INH 配合物存在结构缺陷，这与渗透性结果相关。事实上，PB-INH 在富含盐的水性介质中具有更高的离解速率，因此 INH 通过颊黏膜的转运速率较高。由于分子尺寸较大，其无法通过组织。相反，PCF-INH 在富含盐的水性介质中的离解速率较低，证明其通过组织的转运速率较慢。综上所述，这些结果表明，基于 INH 的金属配合物可以通过颊黏膜途径有效给药，从而影响口服生物利用度和微生物耐药性。
