Effects of ertiprotafib on hepatic cytochrome P450 and peroxisomal enzymes in rats and dogs, and in rat and human primary hepatocytes.
Ertiprotafib (ERTI) significantly increased liver weights in male and female rats, and moderately increased liver weights in male dogs after treatment for 28 days. The present study tested the hypotheses that the organ weight increases were associated with peroxisome proliferation in rats and induction of hepatic enzymes in rats and dogs, and would have limited impacts on humans. At a dosage of 200 mg kg-1 day-1, CYP4A was induced by tenfold in male rats and 2.4-fold in female rats. In male rats, CYP2B was induced by 1.2-fold and CYP3A was induced by 1.7-fold. Palmitoyl CoA oxidase was induced by 5.1-fold in male rats and 2.9-fold in female rats; carnitine acetyltransferase was induced by 10.4-fold in male rats and 5.2-fold in female rats. CYP3A, CYP4A and peroxisomal enzymes were not induced in dogs at 150/200 mg kg-1 day-1. ERTI at 50 microM markedly induced the mRNA level of CYP4A by up to fivefold in rat hepatocytes, but not in human primary hepatocytes. In conclusion, the liver weight increases observed in rats treated with ERTI appears to be due to rodent-specific peroxisome proliferation and the substantial induction of CYP4A1. ERTI is not a potent P450 inducer in dogs or in human hepatocytes. Therefore, ERTI is not expected to exert any significant effects on hepatic drug-metabolizing enzymes in humans.
Tong
Z
Z
Biotransformation Division, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. tongz@wyeth.com
Chandrasekaran
A
A
Jordan
R
R
Markiewicz
V
V
Li
H
H
Xiang
Q
Q
Shen
L
L
Scatina
J
J
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000737:chemistry; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D020675:Peroxisomes / Q000187:drug effects* / Q000201:enzymology*; D010666:Phenylpropionates / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D045162:Thiazolidinediones / Q000737:chemistry; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D013961:Thyroid Gland / Q000187:drug effects / Q000201:enzymology
D007004:Hypoglycemic Agents; D010666:Phenylpropionates; D012333:RNA, Messenger; D045162:Thiazolidinediones; D013876:Thiophenes; C498182:ertiprotafib; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; C063449:zileuton; D006918:Hydroxyurea