title: Brief communication: intraperitoneal galactosamine misdosing as a possible interpretation for responder/nonresponder phenotypes.
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.
authors.affiliation: 1Department of Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: H Roger
authors.initials: HR
authors.lastname: Brown
authors.forename: Kathy
authors.initials: K
authors.lastname: Mellon-Kusibab
authors.forename: Rick
authors.initials: R
authors.lastname: Bertram
authors.forename: Tony
authors.initials: T
authors.lastname: Tillman
authors.forename: Leigh
authors.initials: L
authors.lastname: Arrington-Brown
authors.forename: Holly
authors.initials: H
authors.lastname: Jordan
authors.forename: Lisa
authors.initials: L
authors.lastname: Gates
authors.forename: Richard T
authors.initials: RT
authors.lastname: Miller
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D005260:Female; D005688:Galactosamine / Q000008:administration & dosage* / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008508:Medication Errors; D010641:Phenotype; D051381:Rats
chemical_list: D005688:Galactosamine; D000410:Alanine Transaminase
keywords: drug development; hepatobiliary system; proteomics.