Formation of reactive metabolites of benzbromarone in humanized-liver mice.

Benzbromarone, a uricosuric drug, has the potential to cause serious hepatotoxicity. Several studies have shown the formation of reactive metabolites of benzbromarone and their association with hepatotoxicity in mice. However, it is unknown whether those reactive metabolites are generated in humans in vivo. In the present study, we firstly investigated the pharmacokinetic profiles of benzbromarone in chimeric TK-NOG mice transplanted with human hepatocytes (humanized-liver mice) and then investigated whether reactive metabolites could be generated. The area under the plasma concentration-time curve ratio of benzbromarone and its major metabolites (benzbromarone: 1'-hydroxy benzbromarone: 6-hydroxy benzbromarone) in humanized-liver mice was 1: 1.2: 0.7, which was similar to that reported in humans. In addition, glutathione conjugates and their further metabolites derived from the epoxidation of the benzofuran ring and 1',6-dihydroxylation of benzbromarone were detected in the livers, urine and plasma. Furthermore, their peak intensities in mass spectrometry showed markedly higher levels compared with those of TK-NOG mice. These results suggested that the metabolic profiles of benzbromarone in humanized-liver mice were similar to those in humans and that the reactive metabolites detected in humanized-liver mice could be generated and are associated with the benzbromarone-induced hepatotoxicity in humans.

Novel phenotype in beagle dogs characterized by skin response to compound 48/80 focusing on skin mast cell degranulation.

Beagle dogs have long been employed in toxicology studies and as skin disease models. Compared with other experimental animal species, they are known to be susceptible to skin responses, such as rashes, from exposure to various chemical compounds. Here, a unique dog phenotype was identified that showed no skin response to compound 48/80, a mast cell degranulating agent. Although the skin responses to intradermal injection of polyoxyethylene castor oil derivative (HCO-60, a nonionic detergent), histamine dihydrochloride, concanavalin A (IgE receptor-mediated stimuli), or calcium ionophore A23187 were comparable in wild-type (WT) dogs and these nonresponder (NR) dogs, only the response to compound 48/80 was entirely absent from NR dogs. The skin mast cell density and histamine content per mast cell were histologically comparable between WT and NR dogs. By checking for skin responses to compound 48/80, NR dogs were found to exist at the proportion of 17-20% among four animal breeders. From retrospective analysis of in-house breeding histories, the NR phenotype appears to conform to the Mendelian pattern of recessive inheritance. The standard skin response in WT dogs developed at 2-4 months of age. In conclusion, this unique phenotype, typified by insensitivity in the compound 48/80-induced degranulation pathway in mast cells, has been widely retained by recessive inheritance in beagle dogs among general experimental animal breeders. The knowledge concerning this phenotype could lead to better utilization of dogs in studies and aid in model development.

Pharmacokinetic and pharmacodynamic properties of biapenem, a carbapenem antibiotic, in rat experimental model of severe acute pancreatitis.

OBJECTIVES: It is known that prophylaxis with imipenem reduces the risk of infection accompanying severe acute pancreatitis. In this study,we modified a rat experimental model of severe acute pancreatitis for antibiotic evaluation, and the effect of biapenem was compared with that of imipenem to determine the usefulness of biapenem. METHODS: Severe acute pancreatitis was induced by 5% sodium taurocholate. Antibiotics were subcutaneously administered at 3 and 6 hours and evaluated at 12 hours after the pancreatitis induction. For pharmacokinetic evaluation, antibiotics were subcutaneously administered at 3 hours after the pancreatitis induction. RESULTS: From 3 hours after the induction, bacteria were detected from the pancreas. The total bacterial count increased in a time-dependent manner for 12 hours. Biapenem administration reduced the total bacterial count in the pancreas, as observed in imipenem administration. The plasma concentration of biapenem was almost equivalent to that of imipenem; however, the pancreatic penetration of biapenem was approximately twice that of imipenem in this model. CONCLUSIONS: Biapenem was suggested to be effective in prophylactic treatment of infectious complications as much as imipenem because of its superior penetration to the pancreas in severe acute pancreatitis.