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Open Access 01-12-2015 | Research
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
Published in: Malaria Journal | Issue 1/2015
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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.