Evaluation of an Accurate Mass Approach for the Simultaneous Detection of Drug and Metabolite Distributions via Whole-Body Mass Spectrometric Imaging

Abstract

In drug discovery and development, in vitro absorption and metabolism assays along with in vivo pharmacokinetic (PK), pharmacodynamic (PD), and toxicokinetic (TK) studies are used to evaluate a potential drug candidate. More recently, imaging mass spectrometry approaches have been successfully reported to aid in the preclinical assessment of drug candidates, resulting in the rapid and noteworthy acceptance of the technique in pharmaceutical research. Traditionally, drug distribution studies via mass spectrometric imaging (MSI) are performed as targeted MS/MS analyses, where the analytes of interest, drug and/or metabolite, are known before the imaging experiment is performed. The study presented here describes a whole-body mass spectrometric imaging (WB-MSI) approach using a hybrid MALDI-LTQ-Orbitrap-MS to detect the distribution of reserpine at 2 h post a 20 mg/kg oral dose. This study effectively demonstrates the utility of obtaining accurate mass measurements across a wide mass range combined with postprocessing tools to efficiently identify drug and metabolite distributions without the need for any a priori knowledge.

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

“…Note that when these kinds of measurements are made directly there is a highly heterogeneous distribution of drugs between different cells in the same tissue (e.g., Khatib-Shahidi et al, 2006; Cornett et al, 2008; Nilsson et al, 2010; Römpp et al, 2010, 2011; Castellino et al, 2011; Marko-Varga et al, 2011, 2012; Ait-Belkacem et al, 2012; Shahidi-Latham et al, 2012; El-Mashtoly et al, 2014; Gessel et al, 2014). The PBIN theory explains this straightforwardly in terms of the heterogeneous distribution of transporters, which is both well-known and measurable [see e.g., (http://proteinatlas.org/) (Persson et al, 2006; Pontén et al, 2008)].…”

“…As mentioned above, a great many examples now exist of the heterogeneous distribution of drugs in and between tissues as assessed by imaging mass spectrometry (e.g., Khatib-Shahidi et al, 2006; Cornett et al, 2008; Nilsson et al, 2010; Römpp et al, 2010, 2011; Castellino et al, 2011; Marko-Varga et al, 2011, 2012; Ait-Belkacem et al, 2012; Shahidi-Latham et al, 2012; Rumiato et al, 2013; El-Mashtoly et al, 2014; Gessel et al, 2014). We predict that the imaging of both proteins (or signature peptides derived therefrom) and drugs in the same locations in tissues will continue to be a powerful strategy for assessing which drugs are taken up by which transporters.…”

Mass Spectrometry Imaging of Therapeutics from Animal Models to Three-Dimensional Cell Cultures

“…Various pharmaceutical compounds such as clozapine 22 , erlotinib 23 , olanzapine 24–25 , oxaliplatin 26 , and terfenadine 27 have subsequently been investigated and their metabolites have been imaged in different tissue sections and cells. Figure 1a shows whole-body MSI images generated with a hybrid MALDI-LTQ-Orbitrap-MS to detect the distribution of reserpine and its metabolites at 2 h following a 20 mg/kg oral dose 28 . The results show that reserpine was found to mostly localize in the stomach and testis of the rat.…”

MALDI Imaging Mass Spectrometry—A Mini Review of Methods and Recent Developments

“…Recently, interest in drug imaging has increased. 5,39,40) Imaging of drug distribution is a crucial step in assessing drug function, and currently used methods such as positron emission tomography (PET) or whole body autoradiography (WBA) depend on labeling the drug compound with a radioactive tag. Not only is labeling a costly and time consuming procedure, but also, the subsequent detection process is targeted to the label rather than the drug compound itself, hampering the possibility to find and identify drug metabolites.…”