Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs.
Summary of "Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs."
SHetA2 is a heteroarotinoid that has shown selective inhibition of cancer cell growth and an induction of apoptosis without activation of nuclear retinoic acid receptors. In the rat study, SHetA2 was administered in 1% aqueous methylcellulose/0.2% Tween 80 by oral gavage at 0, 100, 500, and 2,000 mg/kg/day for 28 days. The high-dose administration induced decreased activity in male rats, decreased body-weight gains and food consumption, and changes in organ weights. The major metabolite of SHetA2 in rat plasma was monohydroxy SHetA2, which was considerably higher than the parent compound after oral and intravenous administration. Pharmacokinetic analysis showed extremely low (<1%) systemic bioavailability of SHetA2 for all doses tested. The dose of 2,000 mg/kg/day was considered as the lowest observed adverse effect level. The no observed adverse effect level (NOAEL) was 500 mg/kg/day. In the dog study, no toxicity of SHetA2 in 30% aqueous Solutol(®) HS 15 was observed in any tested dose groups (0, 100, 400, and 1,500 mg/kg/day). The major metabolite of SHetA2 in dog plasma was also monohydroxy SHetA2, which was equal to or lower than the parent compound after oral administration. SHetA2 levels in dog plasma were notably higher, when compared to levels in rat plasma. However, exposure was not dose proportional, as exemplified by a lack of proportional increase in maximum concentration or area under the plasma concentration-time curve with increasing dose. The NOAEL was not established and was considered to be above 1,500 mg/kg/day.
Affiliation
Toxicology Research Laboratory, Department of Pharmacology, University of Illinois at Chicago , Chicago, Illinois , USA.
Journal Details
This article was published in the following journal.
Name: Drug and chemical toxicology
ISSN: 1525-6014
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22947079
- DOI: http://dx.doi.org/10.3109/01480545.2012.710632
Medical and Biotech [MESH] Definitions
Clofenapate
An oral hypolipemic agent in dogs and rats.
Fenretinide
A synthetic retinoid that is used orally as a chemopreventive against prostate cancer and in women at risk of developing contralateral breast cancer. It is also effective as an antineoplastic agent.
Canthaxanthin
A trans-carotenoid pigment widely distributed in nature. The compound is used as an oral suntanning agent and as a food and drug coloring agent. Oral ingestion of the compound causes canthaxanthin retinopathy.
Iproniazid
An irreversible inhibitor of monoamine oxidase types A and B that is used as an antidepressive agent. It has also been used as an antitubercular agent, but its use is limited by its toxicity.
Rats, Long-evans
An outbred strain of rats developed in 1915 by crossing several Wistar Institute white females with a wild gray male. Inbred strains have been derived from this original outbred strain, including Long-Evans cinnamon rats (RATS, INBRED LEC) and Otsuka-Long-Evans-Tokushima Fatty rats (RATS, INBRED OLETF), which are models for Wilson's disease and non-insulin dependent diabetes mellitus, respectively.
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