Renal and hepatic toxicity of a benzopyran-4-one in the Cynomolgus monkey.
The administration of PD 119819, a novel benzopyran-4-one brain dopamine autoreceptor agonist, to Cynomolgus monkeys was followed by deposition of needle-like drug crystals in the bile canaliculi, hepatocytes, proximal renal tubules and renal parenchyma. The crystals were associated with a granulomatous inflammation, and histological and biochemical evidence of hepatic and renal cell damage. Although metabolism differences may be the reason why primates, but not rodents, developed these changes, this form of crystallization appeared to be primarily a result of the insolubility of PD 119189 at alkaline pH.
Macallum
G E
GE
Parke-Davis Research Institute, Warner-Lambert Company, Mississauga, ON, Canada.
Smith
G S
GS
Barsoum
N J
NJ
Walker
R M
RM
Greaves
P
P
D015720:5'-Nucleotidase / Q000097:blood; D000410:Alanine Transaminase / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001578:Benzopyrans / Q000633:toxicity*; D001648:Bile Canaliculi / Q000648:ultrastructure; D001663:Bilirubin / Q000097:blood; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D009954:Ornithine Carbamoyltransferase / Q000378:metabolism; D010879:Piperazines / Q000633:toxicity*; D005723:gamma-Glutamyltransferase / Q000097:blood
D001578:Benzopyrans; D010879:Piperazines; C061602:PD 119819; D003404:Creatinine; D009954:Ornithine Carbamoyltransferase; D005723:gamma-Glutamyltransferase; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D015720:5'-Nucleotidase; D001663:Bilirubin