Mitigating Nephrotoxicity Risks and Ranking Drug Candidates Using MALDI Mass Spectrometry Imaging: A Case Study
Bingming Chen1, Lisa LaFranco-Scheuch1, Shuzhi Dong1
1Merck & Co., Inc., Rahway, New Jersey, USA.
Toxicologic Pathology
|February 27, 2025
Summary
Drug-induced kidney damage is a significant hurdle in drug development. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) helps predict and prevent this by mapping drug distribution in kidneys.
Area of Science:
- Pharmacology
- Toxicology
- Analytical Chemistry
Background:
- Drug-induced nephrotoxicity is a major challenge, causing nearly 25% of severe adverse effects.
- Antimicrobial drugs are implicated in one-third of nephrotoxicity cases.
- Observed nephrotoxicity (renal tubule degeneration, tubular casts) during antibacterial lead optimization.
Purpose of the Study:
- To investigate nephrotoxicity mechanisms and triage drug candidates.
- To utilize matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) for spatial localization of compounds in kidney tissues.
- To establish a correlation between drug distribution and observed nephrotoxicity.
Main Methods:
- Employed MALDI-MSI to analyze compound distribution in rat kidney sections.
- Compared renal distribution patterns of toxic versus non-toxic drug candidates.
- Correlated compound localization with in vivo nephrotoxicity data.
Main Results:
- MALDI-MSI enabled label-free spatial localization of drugs and metabolites in kidney tissues.
- A correlation was found between preferential distribution in the renal cortex/outer medulla and positive in vivo nephrotoxicity for most candidates.
- This correlation aided in ranking compounds for antimicrobial drug discovery.
Conclusions:
- MALDI-MSI is a powerful tool for investigating drug distribution and nephrotoxicity mechanisms.
- The established correlation can facilitate compound triage and derisking during drug discovery and development.
- MALDI-MSI offers a pathway to mitigate drug-induced nephrotoxicity risks.
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