title: Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs.
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.
authors.affiliation: Toxicology Research Laboratory, Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Kasim K
authors.initials: KK
authors.lastname: Kabirov
authors.forename: Izet M
authors.initials: IM
authors.lastname: Kapetanovic
authors.forename: Doris M
authors.initials: DM
authors.lastname: Benbrook
authors.forename: Nancy
authors.initials: N
authors.lastname: Dinger
authors.forename: Irina
authors.initials: I
authors.lastname: Mankovskaya
authors.forename: Alexander
authors.initials: A
authors.lastname: Zakharov
authors.forename: Carol
authors.initials: C
authors.lastname: Detrisac
authors.forename: Marcia
authors.initials: M
authors.lastname: Pereira
authors.forename: Tomás
authors.initials: T
authors.lastname: Martín-Jiménez
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Onua
authors.forename: Aryamitra
authors.initials: A
authors.lastname: Banerjee
authors.forename: Richard B
authors.initials: RB
authors.lastname: van Breemen
authors.forename: Dejan
authors.initials: D
authors.lastname: Nikolić
authors.forename: Lian
authors.initials: L
authors.lastname: Chen
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Lyubimov
mesh_terms: D000284:Administration, Oral; D000311:Adrenal Glands / Q000187:drug effects / Q000473:pathology; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D019540:Area Under Curve; D002839:Chromans / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D004285:Dogs; D004435:Eating / Q000187:drug effects; D005260:Female; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013871:Thiones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D018675:Toxicity Tests; D015430:Weight Gain / Q000187:drug effects
chemical_list: C476105:(((4-nitrophenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methane-1-thione; D016588:Anticarcinogenic Agents; D002839:Chromans; D013871:Thiones