Lesions and identification of crystalline precipitates of glycoprotein IIb-IIIa antagonists in the rat kidney

Two glycoprotein IIb-IIIa antagonists (xemilofiban, SC-54684A, and orbofiba n, SC-57099B), which are platelet aggregation inhibitors, caused crystallin e precipitates in the kidney tubules of rats at high dosages. Dogs were not affected. Depending on the degree of the precipitation, which was dosage d ependent, and the location, which differed somewhat between the two compoun ds, the lesions varied from acute obstruction with tubule cell necrosis, ne phron dilation, and sudden death with no inflammation to severe chronic pyo granulomatous inflammation. In order to understand the relevance of the les ions, it was important to identify the precipitates. This was technically c hallenging because the crystals were water soluble (dissolving in routine f ixing and staining techniques) and were present in insufficient quantity to physically isolate. Techniques were devised to evaluate the crystals in si tu in unstained frozen sections prepared without directly embedding the tis sues in supporting medium, which interfered with the analyses. The crystals were analyzed in situ by infrared and Raman spectroscopy and time-of-fligh t secondary ion mass spectroscopy (TOF-SIMS). Uroliths found in the renal p elvis of one animal were analyzed by liquid chromatography/mass spectrometr y. The resulting spectra showed that the crystals were the de-esterified ac ids of the parent compounds. This knowledge allowed us to predict that the crystalline precipitates would not be a hazard to humans because of the lar ge multiples of the human dosage at which they occurred and because of diff erences in renal physiology between rats, dogs, and humans.