APPLICATION OF NEGATIVE-ION CHEMICAL-IONIZATION ISOTOPE-DILUTION GAS-CHROMATOGRAPHY MASS-SPECTROMETRY TO SINGLE-DOSE BIOAVAILABILITY STUDIES OF MEFLOQUINE

An electron-capture negative-ion chemical ionization gas chromatograph ic-mass spectrometric assay for mefloquine, an antimalarial drug used in the treatment of drug-resistant Plasmodium falciparum malaria, is d escribed. The method, developed in support of bioavailability studies involving the co-administration of different tableted formulations of the drug and an aqueous solution of its C-13(3)-labeled analog, enable s quantification of both dosage forms. Quantitative analysis of extrac ted plasma samples was performed on the O-tert.-butyldimethylsilyl (t- BDMS) derivative of the drug by selected-ion monitoring, using a VG Tr io 2000 quadrupole mass spectrometer and monitoring the [M - t-BDMSOH] ions of the analytes. The method, incorporating [H-2(6)]mefloquine as an internal standard, demonstrated good accuracy and precision over t he 1-200 ng ml(-1) range, with correlation coefficients greater than 0 .990 for all standard curves and a detection level of 50 fg on-column. Replicate analysis of plasma samples over a 90-day period exhibited a mean intra-day and inter-day variation of less than 4.5% and 5.5%, re spectively. The high stability and sensitivity of the assay, combined with the inherent selectivity of mass spectrometric detection, make th e method well-suited for such studies.