title: Clarithromycin enhances the antimalarial efficacy of mefloquine via its increased bioavailability and disrupting P. falciparum apicoplast.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  RESULTS
  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 ∑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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India; Division of Parasitology, CSIR-CDRI, Lucknow, India.
authors.forename: S
authors.initials: S
authors.lastname: Gunjan
authors.affiliation: Division of Parasitology, CSIR-CDRI, Lucknow, India.
authors.forename: S K
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India; Division of Parasitology, CSIR-CDRI, Lucknow, India.
authors.forename: B S
authors.initials: BS
authors.lastname: Chauhan
authors.affiliation: Division of Parasitology, CSIR-CDRI, Lucknow, India.
authors.forename: S K
authors.initials: SK
authors.lastname: Pandey
authors.affiliation: Division of Pharmaceutics, CSIR-CDRI, Lucknow, India.
authors.forename: H
authors.initials: H
authors.lastname: Ahmad
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India; Division of Pharmaceutics, CSIR-CDRI, Lucknow, India.
authors.forename: A K
authors.initials: AK
authors.lastname: Dwivedi
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India; Division of Parasitology, CSIR-CDRI, Lucknow, India. Electronic address: renu1113@rediffmail.com.
authors.forename: R
authors.initials: R
authors.lastname: Tripathi
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D063546:Apicoplasts / Q000187:drug effects*; D001682:Biological Availability; D017291:Clarithromycin / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D006801:Humans; D020128:Inhibitory Concentration 50; D015767:Mefloquine / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D017291:Clarithromycin; D015767:Mefloquine
keywords: Apicoplast; Clarithromycin; Cytochrome P(450); Malaria; Mefloquine