title: Application of negative-ion chemical ionization isotope dilution gas chromatography--mass spectrometry to single-dose bioavailability studies of mefloquine.
abstract: An electron-capture negative-ion chemical ionization gas chromatographic-mass spectrometric assay for mefloquine, an antimalarial drug used in the treatment of drug-resistant Plasmodium falciparum malaria, is described. 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 13C3-labeled analog, enables quantification of both dosage forms. Quantitative analysis of extracted plasma samples was performed on the O-tert.-butyldimethylsilyl (t-BDMS) derivative of the drug by selected-ion monitoring, using a VG Trio 2000 quadrupole mass spectrometer and monitoring the [M-t-BDMSOH]-. ions of the analytes. The method, incorporating [2H6]mefloquine as an internal standard, demonstrated good accuracy and precision over the 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%, respectively. The high stability and sensitivity of the assay, combined with the inherent selectivity of mass spectrometric detection, make the method well-suited for such studies.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
authors.forename: J M
authors.initials: JM
authors.lastname: Neal
authors.forename: W N
authors.initials: WN
authors.lastname: Howald
authors.forename: K L
authors.initials: KL
authors.lastname: Kunze
authors.forename: R F
authors.initials: RF
authors.lastname: Lawrence
authors.forename: W F
authors.initials: WF
authors.lastname: Trager
mesh_terms: D001682:Biological Availability; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods*; D006801:Humans; D007554:Isotopes; D015767:Mefloquine / Q000493:pharmacokinetics*; D015203:Reproducibility of Results
chemical_list: D007554:Isotopes; D015767:Mefloquine