TY - JOUR
T1 - Quantitative Mass Spectrometry Imaging to Study Drug Distribution in the Intestine Following Oral Dosing
AU - Huizing, L.R.S.
AU - McDuffie, J.
AU - Cuyckens, F.
AU - van Heerden, M.
AU - Koudriakova, T.
AU - Heeren, R.M.A.
AU - Vreeken, R.J.
N1 - Funding Information:
This research was part of the M4I research program and received financial support from the Dutch Province of Limburg under the LINK program and the Integrated Technology Strategy (ITS) initiative program of Janssen Pharmaceutica NV. The authors thank Bryn Flinders (DSG, Maastricht, the Netherlands) and Avijt Ghosh (Janssen R&D, Springhouse, USA) for their in-depth discussion.
Funding Information:
This research was part of the M4I research program and received financial support from the Dutch Province of Limburg under the LINK program and the Integrated Technology Strategy (ITS) initiative program of Janssen Pharmaceutica NV. The authors thank Bryn Flinders (DSG Maastricht, the Netherlands) and Avijt Ghosh (Janssen R&D, Springhouse USA) for their in-depth discussion.
Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/2/2
Y1 - 2021/2/2
N2 - Local delivery to the lower gut to treat diseases of the colon has become a topic of special attention. Tissue exposure of locally acting agents is not represented by plasma concentrations. Therefore, reliable methods to measure tissue uptake at the primary site of action (e.g., epithelial layer or lamina propria) are vital. This work investigates the suitability of mass spectrometry imaging (MSI) in quantitatively visualizing intestinal transmural drug distribution. Tofacitinib (Tofa), a drug approved for the treatment of several autoimmune diseases, including ulcerative colitis, was selected as a tool compound for feasibility studies. Oneand 7-h postdose sections of the ileum, proximal- and distal-colon from rats that received an oral solution of Tofa were subjected to matrix-assisted laser desorption ionization (MALDI)-MSI. A dilution series of individual concentrations sprayed over an entire tissue section allowed for tissue type-specific quantitation. At 1 h (systemic T-max), the signal was highest in the ileum, whereas at 7 h, the signal was highest in the colon, when the unabsorbed fraction of the compound reached the colon. A combination of three-dimensional (3D) intensity plots and hematoxylin and eosin (H&E) stains showed a visually observable gradual decrease in Tofa concentration from the lumen toward the muscular layer of the proximal colon. The high luminal concentration of Tofa indicated that flushing of the intestines with saline does not result in complete removal of the drug material from the lumen. This could cause an overestimation of drug concentration in gut tissue homogenates by conventional liquid chromatography-mass spectrometry (LC-MS) methods. This study demonstrates the utility of MSI to differentiate between the lumen and intestinal wall layers and enables proper interpretation of tissue distribution data.
AB - Local delivery to the lower gut to treat diseases of the colon has become a topic of special attention. Tissue exposure of locally acting agents is not represented by plasma concentrations. Therefore, reliable methods to measure tissue uptake at the primary site of action (e.g., epithelial layer or lamina propria) are vital. This work investigates the suitability of mass spectrometry imaging (MSI) in quantitatively visualizing intestinal transmural drug distribution. Tofacitinib (Tofa), a drug approved for the treatment of several autoimmune diseases, including ulcerative colitis, was selected as a tool compound for feasibility studies. Oneand 7-h postdose sections of the ileum, proximal- and distal-colon from rats that received an oral solution of Tofa were subjected to matrix-assisted laser desorption ionization (MALDI)-MSI. A dilution series of individual concentrations sprayed over an entire tissue section allowed for tissue type-specific quantitation. At 1 h (systemic T-max), the signal was highest in the ileum, whereas at 7 h, the signal was highest in the colon, when the unabsorbed fraction of the compound reached the colon. A combination of three-dimensional (3D) intensity plots and hematoxylin and eosin (H&E) stains showed a visually observable gradual decrease in Tofa concentration from the lumen toward the muscular layer of the proximal colon. The high luminal concentration of Tofa indicated that flushing of the intestines with saline does not result in complete removal of the drug material from the lumen. This could cause an overestimation of drug concentration in gut tissue homogenates by conventional liquid chromatography-mass spectrometry (LC-MS) methods. This study demonstrates the utility of MSI to differentiate between the lumen and intestinal wall layers and enables proper interpretation of tissue distribution data.
U2 - 10.1021/acs.analchem.0c03956
DO - 10.1021/acs.analchem.0c03956
M3 - Article
C2 - 33470103
SN - 0003-2700
VL - 93
SP - 2144
EP - 2151
JO - Analytical Chemistry
JF - Analytical Chemistry
IS - 4
ER -