title: Enantioselective determination of ibuprofen in saliva by liquid chromatography/tandem mass spectrometry with chiral electrospray ionization-enhancing and stable isotope-coded derivatization.
abstract: A method was developed and validated for the enantioselective determination of trace ibuprofen (IBU) in saliva using liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) combined with the derivatization using a chiral ESI-enhancing reagent, (S)-1-(4-dimethylaminophenylcarbonyl)-3-aminopyrrolidine (DAPAP), and its isotope-coded analog, (2)H4-DAPAP (d-DAPAP). The DAPAP-derivatization enabled the highly sensitive detection [detection limit, 0.15fmol (equivalent to 30fg of intact IBU) on the column] and complete separation (resolution 3.1) of the IBU enantiomers. The use of d-DAPAP significantly improved the assay precision and accuracy; the intra- (n=5) and inter-assay (n=5) relative standard deviations did not exceed 6.2%, and good accuracy (101.3-106.1%) was obtained. The developed method was successfully applied to the quantitative analysis of IBU in saliva. Using this method, salivary concentration-time profiles of each enantiomer after a single oral administration of the racemic IBU to healthy subjects were obtained. The area under the salivary concentration-time curve of the (S)-enantiomer was ca. twice that of the (R)-enantiomer due to the unidirectional chiral inversion of the (R)- to (S)-enantiomer in vivo. Thus, saliva-based noninvasive pharmacokinetic analyses of IBU enantiomers were achieved by this method.
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Shoujiro
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tadokoro
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Sato
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan. Electronic address: higashi@rs.tus.ac.jp.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Higashi
mesh_terms: D000284:Administration, Oral; D000328:Adult; D002853:Chromatography, Liquid / Q000379:methods; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry*; D007554:Isotopes / Q000737:chemistry; D057230:Limit of Detection; D008297:Male; D012463:Saliva / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry / Q000379:methods; D055815:Young Adult
chemical_list: D007554:Isotopes; D007052:Ibuprofen
keywords: Enantiomeric separation; Ibuprofen; LC/ESI-MS/MS; Saliva; Stable isotope-coded derivatization