title: 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.
authors.affiliation: Chimiothérapie Antiparasitaire, UMR 8076 CNRS BioCIS, Faculté de Pharmacie, Univ Paris-Sud, rue J. B. Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Kaluvu
authors.initials: K
authors.lastname: Balaraman
authors.affiliation: Chimiothérapie Antiparasitaire, UMR 8076 CNRS BioCIS, Faculté de Pharmacie, Univ Paris-Sud, rue J. B. Clément, 92296 Châtenay-Malabry Cedex, France; LETIAM, Groupe de Chimie Analytique de Paris Sud, EA 4041, IUT d'Orsay, Univ Paris Sud 11, Plateau de Moulon, 91400 Orsay, France.
authors.forename: Nashira Campos
authors.initials: NC
authors.lastname: Vieira
authors.affiliation: LETIAM, Groupe de Chimie Analytique de Paris Sud, EA 4041, IUT d'Orsay, Univ Paris Sud 11, Plateau de Moulon, 91400 Orsay, France. Electronic address: fathi.moussa@u-psud.fr.
authors.forename: Fathi
authors.initials: F
authors.lastname: Moussa
authors.affiliation: Drugabilis, 5, rue Jean-Baptiste Clément, 92290 Châtenay-Malabry, France.
authors.forename: Joël
authors.initials: J
authors.lastname: Vacus
authors.affiliation: Chimiothérapie Antiparasitaire, UMR 8076 CNRS BioCIS, Faculté de Pharmacie, Univ Paris-Sud, rue J. B. Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cojean
authors.affiliation: Chimiothérapie Antiparasitaire, UMR 8076 CNRS BioCIS, Faculté de Pharmacie, Univ Paris-Sud, rue J. B. Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Pomel
authors.affiliation: Chimiothérapie Antiparasitaire, UMR 8076 CNRS BioCIS, Faculté de Pharmacie, Univ Paris-Sud, rue J. B. Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Bories
authors.affiliation: Chimie des Substances Naturelles, UMR 8076 CNRS BioCIS, Faculté de Pharmacie, rue J. B. Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Figadère
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras, India.
authors.forename: Ventikasamy
authors.initials: V
authors.lastname: Kesavan
authors.affiliation: Chimiothérapie Antiparasitaire, UMR 8076 CNRS BioCIS, Faculté de Pharmacie, Univ Paris-Sud, rue J. B. Clément, 92296 Châtenay-Malabry Cedex, France. Electronic address: philippe.loiseau@u-psud.fr.
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Loiseau
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D006207:Half-Life; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: C116019:2-propylquinoline; D000981:Antiprotozoal Agents; D011804:Quinolines; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin
keywords: 2-n-propylquinoline; In vitro and in vivo antileishmanial activity; Pharmacokinetics; Toxicity