Pharmacokinetics of dietary phenethyl isothiocyanate in rats.
OBJECTIVE
Phenethyl isothiocyanate (PEITC) is a dietary component present in cruciferous vegetables and reported to have chemopreventive properties. Previous reports of PEITC pharmacokinetics have measured total ITC (PEITC and its metabolites) in plasma. Our objective was to examine the dose-dependent pharmacokinetics and oral bioavailability of unchanged PEITC, as well as its pH- and temperature-dependent stability and its serum protein binding.


METHODS
Stability was studied at different pH values at room temperature and 4 degrees C. Protein binding was determined by equilibrium dialysis. For the pharmacokinetics study, male Sprague-Dawley rats were administered with PEITC at doses of 2, 10, 100, or 400 micromol/kg intravenously or 10 or 100 micromol/kg orally. Plasma samples were analyzed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic analysis was conducted by WinNonlin and ADAPT II.


RESULTS
Phenethyl isothiocyanate was stable in aqueous buffers at pH 7.4 with half-lives of 56.1 and 108 h at room temperature and 4 degrees C, respectively. The free fraction of PEITC in rat serum was 0.019. The clearance (Cl) at a low dose of PEITC (2 micromol/kg) was 0.70 +/- 0.17 L h(-1) kg(-1) with an apparent volume of distribution (Vss) of 1.94 +/- 0.42 L/kg. At higher doses, Cl tended to decrease, whereas Vss increased. Oral bioavailability of PEITC was 115 and 93% at doses of 10 and 100 micromol/kg, respectively. A three-compartment model with Michaelis-Menten elimination and distribution was found to best characterize the plasma concentration profiles.


CONCLUSIONS
Phenethyl isothiocyanate is stable in biological samples, with increased stability under refrigerated conditions. It has high oral bioavailability, low clearance, and high protein binding in rats; nonlinear elimination and distribution occur following the administration of high doses. This investigation represents the first report of the pharmacokinetics of dietary PEITC.
Ji
Yan
Y
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York at Buffalo, 517 Hochstetter Hall, Amherst, New York, 14260, USA.
Kuo
Yuhsin
Y
Morris
Marilyn E
ME
D000284:Administration, Oral; D000818:Animals; D016588:Anticarcinogenic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D017879:Isothiocyanates / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000378:metabolism; D013997:Time Factors
D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D012709:Serum Albumin; C058305:phenethyl isothiocyanate