Automated gas chromatography/tandem mass spectrometry assay for tebufelone and a13C,18O-labeled analog in plasma: Applicability to absolute bioavailability determination

Abstract

An automated capillary gas chromatography/tandem mass spectrometry (GC/MS/MS) assay for the simultaneous quantitation of tebufelone (TE) and 13C, (18)O-labeled TE (TE-CO) in plasma was developed. This method permits the use of stable isotope coadministration (TE and TE-CO dosed concurrently via peroral and intravenous routes, respectively) for the determination of TE absolute bioavailability. The selectivity of MS/MS conducted on a triple-quadrupole instrument allowed minimal sample preparation and rapid analysis. Electron ionization produced molecular ions (M+) for TE, TE-CO, and the 3-methyl-TE internal standard which were selected in Q1 to undergo collisionally activated dissociation in Q2. Quantitation was achieved through monitoring product ions at m/z 248, 251 and 248, respectively, in Q3. A 2-1000 ng per sample (40 pg to 20 ng injected) quantitation range provided access to an effective 1-5000 p.p.b. plasma concentration range (0.2-2 g samples) for both TE and TE-CO. The assay showed no bias and less than 8% relative standard deviation over the entire range. The method was used to determine plasma levels of TE and TE-CO in four dogs receiving 2.5:2.5 mg/kg TE:TE-CO, intravenously. The pharmacokinetics of both isotopomers proved to be identical, indicating no isotope effect and verifying the chemical stability of the (18)O-carbonyl label under these dosing conditions. In addition, the applicability of this analytical approach to the determination of TE peroral bioavailability was initially tested in dogs.

The Absolute Bioavailability and Effect of Food on the Pharmacokinetics of Odanacatib: A Stable-Label i.v./Oral Study in Healthy Postmenopausal Women

“…The i.v. labeled/oral unlabeled approach has been available for some time (Strong et al, 1975), although its use has been relatively limited (Dobson et al, 1994;Bianchetti et al, 1995;Bode et al, 1996;Yeh et al, 1999;Schwab et al, 2013).…”

A Microscale Technique for Gas Chromatography-Mass Spectrometry Measurements of Picogram Amounts of Indole-3-Acetic Acid in Plant Tissues

“…SRM is another method for increased selectivity in MS analysis with multianalyzer instruments (Gaskell and Millington, 1978). This technique involves detection of daughter ions originating from specified, metastable parent ions, resulting in an extremely high specificity that makes the procedure well suited for analysis of trace compounds in biological samples ( e g Chess and Gross, 1980; Thorne and Gaskell, 1985;Dobson et al, 1994;Moritz and Olsen, 1995).…”

Preclinical Bioavailability Assessment of a Poorly Water-Soluble Drug, HGR4113, Using a Stable Isotope Tracer

“…Stable isotopes such as 13 C, 2 H, 15 N, and 18 O have been used to evaluate absolute bioavailability in clinical pharmacokinetics [24][25][26][27][28][29][30][31][32][33][34][35]. Among these, 2 H (deuterium) has been widely used owing to its ease of synthesis [16].…”