Tandem Mass Spectrometry (LC-MS-MS): a Predominant Role in Bioassays for Pharmacokinetic Studies

Abstract

Plasma concentrations of drugs and drug metabolites in bioavailability studies are routinely bioassayed with high performance liquid chromatography (HPLC), gas chromatography (GC), and liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS) methods. In the 1980s and 1990s, HPLC had achieved a relevant role compared to GC and other techniques in pharmacokinetic bioassays. However, in the last few years the LC-MS-MS technique, known as tandem mass spectrometry, has attained a predominant role over all other techniques. This is because it requires a less amount of matrix, possesses better specificity and sensitivity, and requires a shorter operating time. In the experience of the authors, LC-MS-MS in fact requires on average 3-4 fold shorter time to complete a bioequivalence study when performed by one operator than does HPLC. The higher cost of the apparatus and technical assistance of LC-MS-MS are fully compensated by the shorter operating time. Part or most of the HPLC apparatuses have been or are being replaced by LC-MS-MS systems in laboratories operating in clinical and pre-clinical pharmacokinetics and, to a large extent, in those involved in assessing permeability in screening procedures of new chemical entities. This paper analyses the growing development of the LC-MS-MS technique and compares four couples of methods validated with HPLC or GC versus LC-MS-MS, giving analytical details of the two approaches.

Rapid quantification of levosulpiride in human plasma using RP‐HPLC‐MS/MS for pharmacokinetic and bioequivalence study

“…However, these methods possess disadvantages such as long analytical run times or back-extraction procedures for clear separation of levosulpiride, even though they presented sufficiently low lower limits of quantitation (LLOQs) of 0.25-10 ng/mL. Because the need to minimize the analytical time and to maximize the specificity and sensitivity is a key driver in bioanalysis, liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) has recently become the preferred choice for determination of small molecule drugs (Jemal, 2000;Ackermann et al, 2002;Marzo and Bo, 2007;Xu et al, 2007). However, there have been few investigations on LC-MS/MS analysis of levosuliride, except for the report of Paek et al (2004) on the use of hydrophilic interaction liquid chromatography (HILIC)-MS/MS method for the determination of levosulpiride.…”

Quantification of chlordesmethyldiazepam by liquid chromatography–tandem mass spectrometry: application to a cloxazolam bioequivalence study

“…Analytical methods employed for the quantitative determination of drugs and their metabolites in biological samples must generate reproducible and reliable data in order to permit valid interpretation of the studies they support (Stokvis et al, 2005a;Marzo and Dal Bo, 2007;Rozet et al, 2007;Shah, 2007;Xu et al, 2007). During the validation process and routine methodology employment, the internal standard plays an important role in achieving satisfactory accuracy and precision (Stokvis et al, 2005b).…”

“…This technique has led to major breakthroughs in the field of quantitative bioanalysis since the 1990s due to its inherent specificity, sensitivity and speed. It is now generally accepted as the preferred technique for quantitating drugs, metabolites and other biomolecules in biological matrices (Marzo and Dal Bo, 2007;Rozet et al, 2007;Shah, 2007;Xu et al, 2007).…”

Synergic development of pharmacokinetics and bioanalytical methods as support of pharmaceutical research

“…[26][27][28] Tables 1 and 2 show compared conditions to bioassay in human plasma nimesulide and its 4-hydroxy metabolite, and isosorbide-5-mononitrate with chromatographic techniques (HPLC and GC) and tandem mass spectrometry. 2 The advantage of tandem mass spectrometry is evident from the run lasting that is 3-5 times shorter, from the sensitivity that expressed from LLOQ is 2-200 times better and from the time requested to bioassay 1000 analyses, that was 3-4 times shorter.…”