de Jesus Marcelo Bispo, de Matos Alves Pinto Luciana, Fraceto Leonardo Fernandes, Takahata Yuji, Lino Antonio C S, Jaime Carlos, de Paula Eneida
Departamento de Bioquímica, Instituto de Biologia, Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz, s/n, C.P. 6109, 13083-870 Campinas, SP, Brazil.
J Pharm Biomed Anal. 2006 Jun 16;41(4):1428-32. doi: 10.1016/j.jpba.2006.03.010. Epub 2006 May 5.
Praziquantel (PZQ) is a broadly effective anthelminthic drug available for human and veterinary use, being the drug of choice for the treatment of all forms of schistosomiasis. Nevertheless, large doses are required in order to achieve adequate concentrations at the target site due to the poor solubility of PZQ and its significant first pass metabolism. To improve it, avoiding efficiency loss, we have designed a controlled-release system, in which PZQ was encapsulated in beta-cyclodextrin (beta-CD). The inclusion complexes between PZQ/beta-CD were studied at two different stoichiometries 1:1 and 1:2, through experimental and theoretical analysis. Molecular modeling calculations were used to foresee the better stoichiometry of the complex formed as well as the possible orientations of PZQ inside the beta-CD cavity. The complexes prepared were analyzed through H1 two-dimensional nuclear magnetic resonance (H1 2D-NMR) experiments, which provide (evidences) for the 1:1 complexation of PZQ/beta-CD. H1 2D-NMR also revealed details of PZQ/beta-CD molecular interaction, in which the isoquinoline ring of praziquantel is located inside the beta-CD cavity. Finally, phase-solubility diagrams revealed a five-fold increase in praziquantel water solubility upon addition of increasing beta-CD concentrations up to 16 mM, corresponding to the solubility of beta-CD itself. The solubilization profile is consistent with 1:1 stoichiometry of the PZQ/beta-CD complex while the solubilization effect will certainly increase the pharmacological activity of praziquantel.
吡喹酮（PZQ）是一种广泛有效的驱虫药物，可用于人类和兽医领域，是治疗各种形式血吸虫病的首选药物。然而，由于PZQ的溶解度差及其显著的首过代谢，需要大剂量才能在靶部位达到足够的浓度。为了改进这一点并避免效率损失，我们设计了一种控释系统，其中PZQ被包裹在β-环糊精（β-CD）中。通过实验和理论分析，研究了PZQ/β-CD在两种不同化学计量比1:1和1:2下的包合物。分子建模计算用于预测形成的配合物的最佳化学计量比以及PZQ在β-CD腔内的可能取向。通过H1二维核磁共振（H1 2D-NMR）实验对制备的配合物进行分析，该实验为PZQ/β-CD的1:1络合提供了证据。H1 2D-NMR还揭示了PZQ/β-CD分子相互作用的细节，其中吡喹酮的异喹啉环位于β-CD腔内。最后，相溶解度图显示，随着β-CD浓度增加至16 mM（相当于β-CD本身的溶解度），吡喹酮的水溶性增加了五倍。增溶曲线与PZQ/β-CD配合物的1:1化学计量比一致，而增溶效应肯定会增加吡喹酮的药理活性。
