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Imaging MS in Toxicology: An Investigation of Juvenile Rat Nephrotoxicity Associated with Dabrafenib Administration
M Reid Groseclose1, Susan B Laffan, Kendall S Frazier
1Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, NC, 27709, USA.
Abstract:
As part of an investigative nephrotoxicity study, kidney tissues from juvenile rats orally administered dabrafenib at different age intervals between postnatal day (PND) 7 to 35 were investigated by MALDI and LDI imaging mass spectrometry (IMS) to determine the chemical composition of tubular deposits. In the youngest age group (PND 7-13), MALDI IMS demonstrated that a dabrafenib carboxylic acid metabolite was diffusely localized to the regions of tubular deposits (medulla and corticomedullary junction); however, no dabrafenib-related material was detected directly from the deposits. Rather, the LDI IMS analysis determined that the deposits were composed primarily of calcium phosphate. Based on these data, the dabrafenib associated nephrotoxicity, including the formation of tubular deposits, was determined to be age dependent. Furthermore, immature renal function was hypothesized to be responsible for the susceptibility of the youngest pups.
Insights
Kidney toxicity from dabrafenib is age-dependent in juvenile rats. Younger rats showed tubular deposits of calcium phosphate, not the drug itself, indicating immature kidney function contributes to susceptibility.
Area of Science:
- Toxicology
- Pharmacology
- Mass Spectrometry Imaging
Background:
- Nephrotoxicity is a concern with dabrafenib treatment.
- Juvenile animal models are crucial for understanding age-dependent drug effects.
- Tubular deposits in kidneys can indicate adverse drug reactions.
Purpose of the Study:
- To investigate the chemical composition of kidney tubular deposits in juvenile rats exposed to dabrafenib.
- To determine the age-dependency of dabrafenib-induced nephrotoxicity.
- To elucidate the role of immature renal function in drug susceptibility.
Main Methods:
- Juvenile rats (postnatal day 7-35) were orally administered dabrafenib.
- Matrix-assisted laser desorption/ionization (MALDI) and Laser Desorption/Ionization (LDI) imaging mass spectrometry (IMS) were used.
- Kidney tissues were analyzed to identify chemical components of tubular deposits.
Main Results:
- A dabrafenib carboxylic acid metabolite was found in tubular deposit regions in the youngest rats (PND 7-13).
- No dabrafenib-related material was directly detected within the deposits.
- LDI IMS revealed the deposits were primarily composed of calcium phosphate.
- Dabrafenib-associated nephrotoxicity and deposit formation were age-dependent.
Conclusions:
- Dabrafenib-induced nephrotoxicity in juvenile rats is significantly influenced by age.
- Immature renal function in the youngest pups likely contributes to their increased susceptibility.
- The observed tubular deposits consist mainly of calcium phosphate, with dabrafenib metabolites localized nearby.
