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Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs
- Source :
- Drug and Chemical Toxicology. 36:284-295
- Publication Year :
- 2012
- Publisher :
- Informa UK Limited, 2012.
-
Abstract
- 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.
- Subjects :
- Male
No-observed-adverse-effect level
Health, Toxicology and Mutagenesis
Metabolite
Retinoic acid
Administration, Oral
Motor Activity
Pharmacology
Weight Gain
Toxicology
Rats, Sprague-Dawley
Eating
chemistry.chemical_compound
Dogs
Species Specificity
Pharmacokinetics
Adrenal Glands
Toxicity Tests
Animals
Anticarcinogenic Agents
Medicine
Chromans
No-Observed-Adverse-Effect Level
Chemical Health and Safety
business.industry
Prostate
Public Health, Environmental and Occupational Health
Thiones
Organ Size
General Medicine
Rats
Bioavailability
Lowest-observed-adverse-effect level
chemistry
Apoptosis
Area Under Curve
Toxicity
Female
business
Subjects
Details
- ISSN :
- 15256014 and 01480545
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- Drug and Chemical Toxicology
- Accession number :
- edsair.doi.dedup.....c0d269a8c7ec0e41c6ce5f9d1fe487cb