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, b...

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Bibliographic Details
Published in:Toxicologic pathology 2005-10, Vol.33 (6), p.720-725
Main Authors: Greijdanus-van der Putten, Sylvia W. M, van Esch, Eric, Kamerman, Jan, Ballering, Leo A. P., van den Dobbelsteen, Diels J., T de Rijk, Eveline P. C.
Format: Article
Language:English
Subjects:
Alanine Transaminase - blood
Alkaline Phosphatase - blood
Animals
Antipsychotic Agents - administration & dosage
Antipsychotic Agents - toxicity
Bilirubin - blood
Biological and medical sciences
Blood Coagulation - drug effects
Dermatology
Dogs
Dose-Response Relationship, Drug
Feces - chemistry
Female
Hyperplasia
Liver - drug effects
Liver - enzymology
Liver - pathology
Male
Medical sciences
Metabolic diseases
Organ Size - drug effects
Other metabolic disorders
Partial Thromboplastin Time
Pigments (porphyrias, hyperbilirubinemias...)
Porphyrias, Hepatic - chemically induced
Porphyrias, Hepatic - metabolism
Porphyrias, Hepatic - pathology
Protoporphyrins - analysis
Protoporphyrins - metabolism
Skin involvement in other diseases. Miscellaneous. General aspects
Thymus Gland - drug effects
Thymus Gland - pathology
Toxicity Tests
Toxicology
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Summary: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.
ISSN:0192-6233
1533-1601
DOI:10.1080/01926230500351392