Disposition and pharmacokinetics of phenethyl isothiocyanate and 6-phenylhexyl isothiocyanate in F344 rats

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 mu mol/kg (3.71 mu Ci/mu mol) [C-14]PEITC or 50 mu mol/kg (6.59 mu Ci/mu mol) [C-14]PHITC in corn oil. After [C-14]PEITC dosing, whole blood C-14 peaked at 2.9 h, with an elimination half-life (T-1/2e) of 21.7 h; blood C-14 from [C-14]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 [C-14]PHITC and its labeled metabolites were more than twice that for [C-14]PEITC and its labeled metabolites. The effective dose (area under the concentration-time curve) for C-14 from PHITC was greater than 2.5 times the area under the concentration-time curve of C-14 from PEITC in liver, lungs, and several other tissues. During 48 h, approximately 16.5% of the administered dose of [C-14]PHITC was expired as [C-14]CO2, more than 100 times the [C-14]CO2 expired by rats treated with [C-14]PEITC. In rats given [C-14]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 [C-14]PHITC excreted 7.2 +/- 0.8% of the dose of C-14 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.