title: Simultaneous quantification of proposed anti-malarial combination comprising of lumefantrine and CDRI 97-78 in rat plasma using the HPLC-ESI-MS/MS method: application to drug interaction study.
abstract: BACKGROUND
  Lumefantrine is the mainstay of anti-malarial combination therapy in most endemic countries presently. However, it cannot be used alone owing to its long onset time of action. CDRI 97-78 is a promising trioxane-derivative anti-malarial candidate that is currently being investigated as a substitute for artemisinin derivatives owing to their emerging resistance.
  
  
  METHODS
  In the present study, a sensitive, simple and rapid high-performance liquid chromatography coupled with positive ion electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method was developed for the simultaneous determination of lumefantrine and CDRI 97-78's metabolite, 97-63, in rat plasma using halofantrine as an internal standard. Lumefantrine and 97-63 were separated on a Waters Atlantis C18 (4.6×50 mm, 5.0 μm) column under isocratic condition with mobile phase consisting of acetonitrile: methanol (50:50, v/v) and ammonium formate buffer (10 mM, pH 4.5) in the ratio of 95:5 (v/v) at a flow rate of 0.65 mL/min.
  
  
  RESULTS
  The method was accurate and precise within the linearity range 3.9-500 ng/mL for both lumefantrine and 97-63 with a correlation coefficient (r2) of ≥0.998. The intra- and inter-day assay precision ranged from 2.24 to 7.14% and 3.97 to 5.90%, and intra- and inter-day assay accuracy was between 94.93 and 109.51% and 96.87 and 108.38%, respectively, for both the analytes. Upon coadministration of 97-78, the relative bioavailability of lumefantrine significantly decreased to 64.41%.
  
  
  CONCLUSIONS
  A highly sensitive, specific and reproducible high-throughput LC-ESI-MS/MS assay was developed and validated to quantify lumefantrine and CDRI 97-78. The method was successfully applied to study the effect of oral co-administration of lumefantrine on the pharmacokinetics of 97-78 in male Sprague-Dawley rats and vice versa. Co-administration of 97-78 significantly decreased the systemic exposure of lumefantrine.
authors.affiliation: Academy of Scientific and Industrial Research, New Delhi, India. wahajuddin@gmail.com.|Pharmacokinetics and Metabolism Division, CSIR- Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India. wahajuddin@gmail.com.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Wahajuddin
authors.affiliation: Analytical Chemistry Division, CSIR-Indian Institute of Toxicology Research, Lucknow, 226001, Uttar Pradesh, India. shilu1july@gmail.com.
authors.forename: Sheelendra P
authors.initials: SP
authors.lastname: Singh
authors.affiliation: Academy of Scientific and Industrial Research, New Delhi, India. isha6taneja@gmail.com.|Pharmacokinetics and Metabolism Division, CSIR- Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India. isha6taneja@gmail.com.
authors.forename: Isha
authors.initials: I
authors.lastname: Taneja
authors.affiliation: Academy of Scientific and Industrial Research, New Delhi, India. ksrraju.phm@gmail.com.|Pharmacokinetics and Metabolism Division, CSIR- Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India. ksrraju.phm@gmail.com.
authors.forename: Kanumuri S R
authors.initials: KS
authors.lastname: Raju
authors.affiliation: Academy of Scientific and Industrial Research, New Delhi, India. jr.gayen@cdri.res.in.|Pharmacokinetics and Metabolism Division, CSIR- Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India. jr.gayen@cdri.res.in.
authors.forename: Jiaur R
authors.initials: JR
authors.lastname: Gayen
authors.affiliation: Faculty of Pharmacy, Integral University, Lucknow, India. hefazats@hotmail.com.
authors.forename: Hefazat H
authors.initials: HH
authors.lastname: Siddiqui
authors.affiliation: Academy of Scientific and Industrial Research, New Delhi, India. sk_singh@cdri.res.in.|Pharmacokinetics and Metabolism Division, CSIR- Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India. sk_singh@cdri.res.in.
authors.forename: Shio K
authors.initials: SK
authors.lastname: Singh
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000097:blood* / Q000493:pharmacokinetics; D001774:Blood Chemical Analysis / Q000295:instrumentation / Q000379:methods*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000097:blood* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004338:Drug Combinations; D004983:Ethanolamines / Q000097:blood* / Q000493:pharmacokinetics; D005449:Fluorenes / Q000097:blood* / Q000493:pharmacokinetics; D000078102:Lumefantrine; D008297:Male; D010616:Phenanthrenes / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
chemical_list: D000962:Antimalarials; D019086:Bridged Bicyclo Compounds, Heterocyclic; C574493:CDRI-97-78; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D010616:Phenanthrenes; D000078102:Lumefantrine; C023768:halofantrine