Brief Communication: Intraperitoneal Galactosamine Misdosing as a Possible Interpretation for Responder/Nonresponder Phenotypes. (April 2014)

• Record Type: Journal Article
• Authors: Brown, H. Roger; Mellon-Kusibab, Kathy; Bertram, Rick; Tillman, Tony; Arrington-Brown, Leigh; Jordan, Holly; Gates, Lisa; Miller, Richard T.
• Is Part Of: Toxicologic pathology. Volume 42:Number 3(2014:Apr.)
• Page Start: 622
• Page End: 625
• Publication Date: 2014-04
• Subjects: drug development -- hepatobiliary system -- proteomics.; Pathology -- Periodicals; Toxicology -- Periodicals; Pathology; Toxicology; 615.9
• DOI: 10.1177/0192623313495602
• Languages: English
• ISSNs: 0192-6233

Abstract

Previous reports investigating the mechanisms of galactosamine toxicity have discussed the presence of responders and nonresponders after intraperitoneal (IP) administration of a toxic dose. The incidence of nonresponders has been reported to be as high as 47%. To rule out inadvertent intestinal, solid organ, or subcutaneous injection as at least a partial cause for the variability, we performed midline incisions and dosed 10 rats via a flexible catheter, with a toxic dose of galactosamine. Results were compared to a previous range finding study with IP-injected rats. As opposed to the IP-injected rats that had a roughly 50% response rate (based on serum alanine aminotransferase [ALT] elevation) and 100% of the midline incision catheter-instilled rats had elevations in ALT. Saline controls had no elevations. Histopathologic examination of livers from 5 midline-incisioned rats euthanized 48 hr after dosing with the lowest ALT responses revealed portal eosinophilic infiltrates and biliary hypertrophy/hyperplasia contiguous with areas of necrosis. Examination of 5 rats with the highest ALT elevations euthanized 10 days post dose revealed similar lesions to be resolving. We conclude that a significant contribution to variability in response to IP-injected galactosamine and possibly other investigative drugs is inadvertent misinjection of all or part of the dose.