Clarithromycin enhances the antimalarial efficacy of mefloquine via its increased bioavailability and disrupting P. falciparum apicoplast

Abstract Aim Many important drugs like mefloquine are not being used because of the development of resistance and other related issues. In the present study, we aimed to control drug resistance by using combination therapy and tried to understand the mechanism involved. Material and methods We have explored in vitro interaction of clarithromycin (CLTR), and mefloquine (MQ) against Pf3D7 and PfK1 strains. Bioavailability of MQ in parasitized RBC lysate was checked in the presence/absence of CLTR using HPLC method. Further tufA mRNA/protein expression was investigated to know the effect of both drugs on apicoplast by using qPCR and Western blotting. Key findings MQ and CLTR inhibited growth of Pf3D7 and PfK1. CLTR showed its delayed antimalarial effect by its low IC₅₀ values in the second cycle which indicates its effect on apicoplast. Downregulation of tufA expression on both mRNA and protein level supports this hypothesis. MQ and CLTR showed synergism/additiveness (mean Σ FICs = 0.89 and 1.26) against Pf3D7 and PfK1 respectively. It is evidenced from HPLC data that CLTR might have reduced metabolism of MQ in Plasmodium falciparum, leading to increased levels of MQ to produce enhanced antimalarial activity. The metabolism of CLTR is also reduced may be due to competitive metabolism of MQ via CYP3A4. Significance The present study reveals that broad spectrum biological activities (i.e. antimalarial and antiviral) of MQ can be saved by using suitable partner drug like CLTR. This study also shows that CLTR increases the concentration of MQ and disrupts the apicoplast.