Repeated oral administration modulates the pharmacokinetic behavior of the chemopreventive agent phenethyl isothiocyanate in rats

The principal objective of this study was to evaluate whether repeated oral administration influences the pharmacokinetic behavior of the chemopreventive agent phenethyl isothiocyanate (PEITC) in rat. Animals were treated orally with 0.5, 1.0 and 5.0 mg/kg of the isothiocyanate for 4 days, and plasma levels at various times post-administration were determined by LC/MS after the first and last day. To determine absolute bioavailability, a group of animals was treated with a single (0.5 mg/kg) intravenous dose of PEITC. Following single oral dose administration, PEITC was rapidly absorbed, peak plasma concentrations being attained within the hour, and achieved an absolute bioavailability of 77%, but displayed dose-dependent pharmacokinetics, with bioavailability decreasing and clearance increasing moderately with dose; C(max) values did not rise proportionately to the dose and volume of distribution increased. At the higher doses of 1.0 and 5.0 mg/kg, repeated administration led to higher PEITC plasma C(max) concentrations and decreased plasma clearance of the isothiocyanate leading to enhanced bioavailability.