The Postnatal Resolution of Developmental Toxicity Induced by Pharmacological Diacylglycerol Acyltransferase 2 (DGAT2) Inhibition During Gestation in Rats.

Autor:	Catlin NR; Drug Safety Research, Development, & Medical, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, USA., Bowman CJ; Drug Safety Research, Development, & Medical, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, USA., Campion SN; Drug Safety Research, Development, & Medical, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, USA., Lewis EM; Charles River Laboratories, Inc., Safety Assessment, Horsham, Pennsylvania 19044, USA., Nowland WS; Drug Safety Research, Development, & Medical, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, USA., Stethem C; Drug Safety Research, Development, & Medical, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, USA., Cappon GD; Drug Safety Research, Development, & Medical, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, USA.
Jazyk:	angličtina
Zdroj:	Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2022 Sep 24; Vol. 189 (2), pp. 225-236.
DOI:	10.1093/toxsci/kfac077
Abstrakt:	Ervogastat (PF-06865571) is a small molecule diacylglycerol acyltransferase 2 (DGAT2) inhibitor being developed for the oral treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis. DGAT2 is a key enzyme in triglyceride synthesis in tissues and in regulating energy metabolism. Fertility and developmental toxicity studies with ervogastat were conducted in female rats and rabbits. There were no effects on female rat fertility or rabbit embryo-fetal development. Administration of ervogastat to pregnant rats during organogenesis reduced fetal weight and caused higher incidences of bent bones in fetuses that were shown to resolve by postnatal day 28 and were therefore considered to be transient variations secondary to developmental delay. Extended dosing in rats through the end of gestation and lactation (pre- and post-natal development study) caused impaired skin development, reduced offspring viability, and growth retardation. The spectrum of developmental effects in rats is consistent with the intended pharmacology (altered triglyceride metabolism) and the transient nature of the skeletal findings, along with the late gestational window of sensitivity for the effects on skin barrier development, reduce the concern for potential adverse developmental effects following unintended early gestational exposure to ervogastat in humans where treatment can be discontinued once pregnancy is determined. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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