Pharmacokinetics of Dietary Phenethyl Isothiocyanate in Rats
- 515 Downloads
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.
Stability was studied at different pH values at room temperature and 4°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 μmol/kg intravenously or 10 or 100 μmol/kg orally. Plasma samples were analyzed by liquid chromatography–tandem mass spectrometry. Pharmacokinetic analysis was conducted by WinNonlin and ADAPT II.
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°C, respectively. The free fraction of PEITC in rat serum was 0.019. The clearance (Cl) at a low dose of PEITC (2 μmol/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 μmol/kg, respectively. A three-compartment model with Michaelis–Menten elimination and distribution was found to best characterize the plasma concentration profiles.
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.
Key Wordsbioavailability PEITC pharmacokinetics phenethyl isothiocyanate protein binding rats stability
area under the plasma concentration vs. time curve
breast cancer resistance protein
maximal plasma concentration
the unbound fraction
absorption rate constant
degradation rate constant
multidrug resistance-associated protein
glutathione conjugate of PEITC
time to reach Cmax
volume of distribution
This work was funded by U.S. Army Breast Cancer Research Program Contract DAMD17-00-1-0376 and DAMD 17-03-1-0527. We acknowledge Qi Wang for synthesizing 14C-PEITC and David Soda for technical assistance.
- 2.Getahun, S. M., Chung, F. L. 1999Conversion of glucosinolates to isothiocyanates in humans after ingestion of cooked watercressCancer Epidemiol. Biomark. Prev.8447451Google Scholar
- 4.D. C. P. C. NCI.1996Clinical development plan: phenethyl isothiocyanateJ. Cell. Biochem., Suppl.26149157Google Scholar
- 5.Hecht, S. S. 1995Chemoprevention by isothiocyanatesJ. Cell. Biochem., Suppl.22195209Google Scholar
- 16.Chung, F. L., Morse, M. A., Eklind, K. I., Lewis, J. 1992Quantitation of human uptake of the anticarcinogen phenethyl isothiocyanate after a watercress mealCancer Epidemiol. Biomark. Prev.1383388Google Scholar
- 18.Liebes, L., Conaway, C. C., Hochster, H., Mendoza, S., Hecht, S. S., Crowell, J., Chung, F. L. 2001High-performance liquid chromatography-based determination of total isothiocyanate levels in human plasma: application to studies with 2-phenethyl isothiocyanateAnal. Biochem.291279289CrossRefPubMedGoogle Scholar
- 22.Taipalensuu, J., Tornblom, H., Lindberg, G., Einarsson, C., Sjoqvist, F., Melhus, H., Garberg, P., Sjostrom, B., Lundgren, B., Artursson, P. 2001Correlation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayersJ. Pharmacol. Exp. Ther.299164170PubMedGoogle Scholar
- 26.Tookey, H. L., Etten, C. H., Daxenbichler, M. E 1980GlucosinolatesLiener, I. E. eds. Toxic Constituents of Plant Foodstuffs2Academic PressNew York103142Chap. 4Google Scholar
- 27.Negrusz, A., Moore, C. M., McDonagh, N. S., Woods, E. F., Crowell, J. A., Levine, B. S. 1980Determination of phenethylamine, a phenethyl isothiocyanate marker, in dog plasma using solid-phase extraction and gas chromatography–mass spectrometry with chemical ionizationJ. Chromatogr., B, Biomed. Sci. Appl.718193198Google Scholar