In vitro and in vivo antileishmanial properties of a 2-n-propylquinoline hydroxypropyl β-cyclodextrin formulation and pharmacokinetics via intravenous route

Abstract

2-n-propylquinoline (2-n-PQ) had shown interesting in vivo antileishmanial activities after administration by oral route on leishmaniasis animal models. However, the lipophilic properties of this compound avoid its use by intravenous route, this route being indicated in cases of severe visceral leishmaniasis with vomiting. Thus, a 2-n-propylquinoline hydroxypropyl beta-cyclodextrin (2-n-PQ-HPC) formulation was set up in this aim. The formulation was active in vitro both on Leishmania donovani axenic and intramacrophage amastigotes with IC50 values at 6.22±0.82μM and 20.01±0.52μM, respectively, without any toxicity on macrophages. 2-n-PQ-HPC exhibited similar activity on WT and drug-resistant parasites. Its in vitro interactions with antimonials, amphotericin B and miltefosine were found as additive both in axenic amastigotes and intramacrophage amastigotes. 2-n-PQ-HPC was not able to generate drug resistance after in vitro drug pressure since the resistance index was less than 4. 2-n-PQ-HPC was also active on the L. donovani/Balb/c mice model with an intravenous treatment regimen at 10mgkg(-1)day(-1) on 10 consecutive days without hepatic, renal and blood toxicity. The pharmacokinetics of 2-n-PQ in rats showed that after an intravenous treatment of the formulation at 10mgkg(-1), the plasma drug concentrations rapidly declined bi-exponentially with a half-life of 58.7min and a total clearance of 18.63lh(-1)kg(-1). The apparent volume of distribution was higher than the blood volume in rats, indicating that 2-n-PQ was well distributed in tissues, allowing parasite elimination. Such a formulation is worth of further antiparasitic and toxicological evaluations.

Keywords: 2-n-propylquinoline; In vitro and in vivo antileishmanial activity; Pharmacokinetics; Toxicity.