Drug-induced protoporphyria in beagle dogs.
As part of regulatory safety testing program, a 13-week oral toxicity study with a new antipsychotic drug candidate was performed in beagle dogs. During this study, dark red/brown feces were recorded in treated dogs and increases in liver parameters (alanine aminotransferase, alkaline phosphatase, bilirubin) were measured biochemically. At the end of the study, livers of high-dose (50 mg/kg) animals were (mottled) dark brown, sometimes with pale foci. Histopathological examination of these livers showed dark globular pigment deposits in the hepatocellular cytoplasm and within the bile canaliculi. Varying numbers of inflammatory cell infiltrates were additionally present in association with the deposits. These pigment deposits showed birefringency with characteristic "Maltese Cross"-like structures under polarized light. Electronmicroscopy revealed the typical, so-called "sunburst" pattern with radiating double-lined crystalline structures. These morphologic characteristics strongly indicated at the presence of porphyrins, which was definitely confirmed biochemically. Published reports of drug-induced hepatic porphyria in dogs are rare. The possible underlying mechanism in the dog and man is discussed.
Greijdanus-van der Putten
Sylvia W M
SW
Organon, Department of Toxicology and Drug Disposition, Oss, The Netherlands. sylvia.greijdanus@organon.com
van Esch
Eric
E
Kamerman
Jan
J
Ballering
Leo A P
LA
van den Dobbelsteen
Diels J
DJ
T de Rijk
Eveline P C
EP
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001663:Bilirubin / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D005260:Female; D006965:Hyperplasia; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010314:Partial Thromboplastin Time; D017094:Porphyrias, Hepatic / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011524:Protoporphyrins / Q000032:analysis / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D018675:Toxicity Tests
D014150:Antipsychotic Agents; D011524:Protoporphyrins; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin