Abstract

Naturally occurring phenethyl isothiocyanate (PEITC) and its synthetic homolog 6-phenylhexyl isothiocyanate (PHITC) are both effective inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumor development in A/J mice and F344 rats. To help explain why PHITC is considerably more efficacious than PEITC in chemopreventive potency, comparative disposition and pharmacokinetics data for male F344 rats were obtained after a single gavage dose of 50 μmol/kg (3.71 μCi/μmol) [¹⁴C]PEITC or 50 μmol/kg (6.59 μCi/μmol) [¹⁴C]PHITC in corn oil. After [¹⁴C]PEITC dosing, whole blood ¹⁴C peaked at 2.9 h, with an elimination half-life (T_1/2e) of 21.7 h; blood ¹⁴C from [¹⁴C]PHITC-treated rats peaked at 8.9 h, with an T_1/2e of 20.5 h. In lungs, the target organ, the T_1/2e for [¹⁴C]PHITC and its labeled metabolites were more than twice that for [¹⁴C]PEITC and its labeled metabolites. The effective dose (area under the concentration-time curve) for ¹⁴C from PHITC was greater than 2.5 times the area under the concentration-time curve of¹⁴C from PEITC in liver, lungs, and several other tissues. During 48 h, approximately 16.5% of the administered dose of [¹⁴C]PHITC was expired as [¹⁴C]CO₂, more than 100 times the [¹⁴C]CO₂ expired by rats treated with [¹⁴C]PEITC. In rats given [¹⁴C]PEITC, 88.7 ± 2.2% and 9.9 ± 1.9% of the dose appeared in the urine and feces, respectively, during 48 h; however, rats given [¹⁴C]PHITC excreted 7.2 ± 0.8% of the dose of¹⁴C in urine and 47.4 ± 14.0% in the feces. Higher effective doses of PHITC in the lungs and other organs may be the basis, in part, for its greater potency as a chemopreventive agent.