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Lesions and Identification of Crystalline Precipitates of Glycoprotein IIb-IIIa Antagonists in the Rat Kidney

Monsanto/Searle Research and Development, 4901 Searle Parkway (J-3), Skokie, Illinois 60077, stuart.levin{at}monsanto.com.

Robert M. Friedman

Monsanto/Searle Research and Development, Creve Coeur, Missouri 63141

Enriqueta Cortez

Monsanto/Searle Research and Development, Creve Coeur, Missouri 63141

Jeremy Hribar

Monsanto/Searle Research and Development, Skokie, Illinois 60077

Mark Nicholas

Evans East Co., Plainsboro, New Jersey 08536

Sally Schlessinger

Monsanto/Searle Research and Development, Skokie, Illinois 60077

Monique Fouant

Monsanto/Searle Research and Development, Skokie, Illinois 60077

Nasir Khan

Monsanto/Searle Research and Development, Skokie, Illinois 60077

Two glycoprotein IIb-IIIa antagonists (xemilofiban, SC-54684A, and orbofiban, SC-57099B), which are platelet aggregation inhibitors, caused crystalline precipitates in the kidney tubules of rats at high dosages. Dogs were not affected. Depending on the degree of the precipitation, which was dosage dependent, and the location, which differed somewhat between the two compounds, the lesions varied from acute obstruction with tubule cell necrosis, nephron dilation, and sudden death with no inflammation to severe chronic pyogranulomatous inflammation. In order to understand the relevance of the lesions, it was important to identify the precipitates. This was technically challenging because the crystals were water soluble (dissolving in routine fixing and staining techniques) and were present in insufficient quantity to physically isolate. Techniques were devised to evaluate the crystals in situ in unstained frozen sections prepared without directly embedding the tissues in supporting medium, which interfered with the analyses. The crystals were analyzed in situ by infrared and Raman spectroscopy and time-of-flight secondary ion mass spectroscopy (TOF-SIMS). Uroliths found in the renal pelvis of one animal were analyzed by liquid chromatography/mass spectrometry. The resulting spectra showed that the crystals were the de-esterified acids of the parent compounds. This knowledge allowed us to predict that the crystalline precipitates would not be a hazard to humans because of the large multiples of the human dosage at which they occurred and because of differences in renal physiology between rats, dogs, and humans.

Key Words: Xemilofiban • orbofiban • TOF-SIMS • Raman spectroscopy • infrared spectroscopy • LC/MS

Toxicologic Pathology, Vol. 27, No. 1, 38-43 (1999)
DOI: 10.1177/019262339902700108


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