Decrease of intestinal P-glycoprotein activity by 2 n-propylquinoline, a new oral treatment for visceral leishmaniasis

Abstract

Drugs currently available for visceral leishmaniasis treatment are potentially toxic, have to be administered by parenteral route and frequently give rise to drug resistance, due to the involvement of P-glycoproteins (P-gp) in Leishmania. The purpose of this study was to investigate a possible inhibitory effect of 2 n-propylquinoline (2 nPQ) on P-gp activity. 2 nPQ is a new oral anti-leishmanial drug that has demonstrated its efficacy in BALB/c infected mice with Leishmania donovani [Antimicrob. Agents Chemother. 37 (1993) 859]. Rat everted gut sacs and human intestinal Caco-2 cell lines were used to study the effect of 2 nPQ on P-gp activity. Our results demonstrate an inhibitory effect of 2 nPQ on the P-gp activity with two P-gp substrates (rhodamine 123 and digoxin), two P-gp inhibitors (cyclosporin A and verapamil), and in two different species. Alone or associated with other active drugs, 2 nPQ would be very useful to control Leishmania Multi-Drug-Resistance and intestinal P-gp in humans with kala-azar. Index Descriptors and Abbreviations: VL, visceral leishmaniasis; 2 nPQ, 2 n-propylquinoline; P-gp, P-glycoprotein; MDR, Multi-Drug-Resistance; Caco-2 cells, human colon adenocarcinoma cell line; BALB/c, Consanguine mouse; HIV, human immunodeficiency virus; DMEM, Dulbecco’s modified Eagle’s medium; PBS, phosphate-buffered salt Galipea longiflora, Rutaceae plant rat; everted gut sacs; LD 50, lethal dose 50.