Mass Spectrometry Imaging of Cassette-Dosed Drugs for Higher Throughput Pharmacokinetic and Biodistribution Analysis

Abstract

Cassette dosing of compounds for preclinical drug plasma pharmacokinetic analysis has been shown to be a powerful strategy within the pharmaceutical industry for increasing throughput while decreasing the number of animals used. Presented here for the first time is data on the application of a cassette dosing strategy for label-free tissue distribution studies. The aim of the study was to image the spatial distribution of eight nonproprietary drugs (haloperidol, bufuralol, midazolam, clozapine, terfenadine, erlotinib, olanzapine, and moxifloxacin) in multiple tissues after oral and intravenous cassette dosing (four compounds per dose route). An array of mass spectrometry imaging technologies, including matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI), liquid extraction surface analysis tandem mass spectrometry (LESA-MS/MS), and desorption electrospray ionization mass spectrometry (DESI-MS) was used. Tissue analysis following intravenous and oral administration of discretely and cassette-dosed compounds demonstrated similar relative abundances across a range of tissues indicating that a cassette dosing approach was applicable. MALDI MSI was unsuccessful in detecting all of the target compounds; therefore, DESI MSI, a complementary mass spectrometry imaging technique, was used to detect additional target compounds. In addition, by adapting technology used for tissue profiling (LESA-MS/MS) low spatial resolution mass spectrometry imaging (∼1 mm) was possible for all targets across all tissues. This study exemplifies the power of multiplatform MSI analysis within a pharmaceutical research and development (R&D) environment. Furthermore, we have illustrated that the cassette dosing approach can be readily applied to provide combined, label-free pharmacokinetic and drug distribution data at an early stage of the drug discovery/development process while minimizing animal usage.

Ambient Mass Spectrometry Imaging Using Direct Liquid Extraction Techniques

“…40 Meanwhile, LESA MS/MS experiments performed in MRM mode have been used for imaging drugs in tissue sections with a spatial resolution of ~1 mm. 97 Key findings from these studies will be discussed in the next sections.…”

“…97 To increase throughput and potentially reduce costs, Swales et al simultaneously administered four drugs to a rat model. 97 MSI was performed on rat brain and kidney tissue sections post drug administration at two time points. Figure 6G shows LESA MS/MS images of four drug compounds in rat kidney at 2 and 6 hours post dosing.…”

“…The study concluded that the strategy of dosing multiple drugs simultaneously successfully enabled both pharmacokinetic and distribution data using fewer resources. 97 …”

Drug compound characterization by mass spectrometry imaging in cancer tissue

“…Recently, high resolution MSI provided a significant advantage of autoradiography from the aspect of the drug metabolites (Fehniger et al 2011;Jirasko et al 2014;Liu et al 2013;Buck et al 2015) and demonstrated the distribution of a confirmed drug metabolite that possibly lead to the drug toxicity (Török et al 2015). The technology is today making important contributions in fields such as PK screening (Castellino et al 2013), novel pro-drug concepts (Nilsson et al 2010;Fehniger et al 2011), drug delivery systems (DDS) by micellar nanoparticle formulation (Swales et al 2014), biomarkers for PD (Yasunaga et al 2013;Shariatgorji et al 2014;Cobice et al 2013) as well as proteomics (Goto et al 2014;Ye et al 2014). MSI ultimately leads to a better understanding of ADME, PK/PD and TK/TD.…”

Spatial Quantitation of Drugs in tissues using Liquid Extraction Surface Analysis Mass Spectrometry Imaging

“…LESA-MSI is a surface sampling technique that has been shown to be widely applicable and sensitive but can deliver only low spatial resolution images (typically 1000 μm)11. The technique can be combined with Orbitrap or time of flight mass spectrometers for effective use as a profiling tool15 but has also been used effectively with high sensitivity triple quadrupole mass spectrometers operated in selected reaction monitoring mode for mass spectrometry imaging16.…”