Pharmaceutical Research

, Volume 22, Issue 10, pp 1658–1666 | Cite as

Pharmacokinetics of Dietary Phenethyl Isothiocyanate in Rats

Research Paper


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 Words

bioavailability 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


phenethyl isothiocyanate


glutathione conjugate of PEITC


room temperature


time to reach Cmax


elimination half-life


degradation half-life


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.


  1. 1.
    Fenwick, G. R., Heaney, R. K., Mullin, W. J. 1983Glucosinolates and their breakdown products in food and food plantsCrit. Rev. Food Sci. Nutr.18123201PubMedGoogle Scholar
  2. 2.
    Getahun, S. M., Chung, F. L. 1999Conversion of glucosinolates to isothiocyanates in humans after ingestion of cooked watercressCancer Epidemiol. Biomark. Prev.8447451Google Scholar
  3. 3.
    Talalay, P., Fahey, J. W. 2001Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolismJ. Nutr.1313027S3033SPubMedGoogle Scholar
  4. 4.
    D. C. P. C. NCI.1996Clinical development plan: phenethyl isothiocyanateJ. Cell. Biochem., Suppl.26149157Google Scholar
  5. 5.
    Hecht, S. S. 1995Chemoprevention by isothiocyanatesJ. Cell. Biochem., Suppl.22195209Google Scholar
  6. 6.
    Zhang, Y., Talalay, P. 1994Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanismsCancer Res.541976s1981sPubMedGoogle Scholar
  7. 7.
    Yu, R., Mandlekar, S., Harvey, K. J., Ucker, D. S., Kong, A. N. 1998Chemopreventive isothiocyanates induce apoptosis and caspase-3-like protease activityCancer Res.58402408PubMedGoogle Scholar
  8. 8.
    Gamet-Payrastre, L., Li, P., Lumeau, S., Cassar, G., Dupont, M. A., Chevolleau, S., Gasc, N., Tulliez, J., Terce, F. 2000Sulforaphane, a naturally occurring isothiocyanate, induces cell cycle arrest and apoptosis in HT29 human colon cancer cellsCancer Res.6014261433PubMedGoogle Scholar
  9. 9.
    Xu, K., Thornalley, P. J. 2000Studies on the mechanism of the inhibition of human leukaemia cell growth by dietary isothiocyanates and their cysteine adducts in vitroBiochem. Pharmacol.60221231CrossRefPubMedGoogle Scholar
  10. 10.
    Brusewitz, G., Cameron, B. D., Chasseaud, L. F., Gorler, K., Hawkins, D. R., Koch, H., Mennicke, W. H. 1977The metabolism of benzyl isothiocyanate and its cysteine conjugateBiochem. J.16299107PubMedGoogle Scholar
  11. 11.
    Gorler, K., Krumbiegel, G., Mennicke, W. H., Siehl, H. U. 1982The metabolism of benzyl isothiocyanate and its cysteine conjugate in guinea-pigs and rabbitsXenobiotica12535542PubMedGoogle Scholar
  12. 12.
    Mennicke, W. H., Gorler, K., Krumbiegel, G. 1983Metabolism of some naturally occurring isothiocyanates in the ratXenobiotica13203207PubMedGoogle Scholar
  13. 13.
    Ioannou, Y. M., Burka, L. T., Matthews, H. B. 1984Allyl isothiocyanate: comparative disposition in rats and miceToxicol. Appl. Pharmacol.75173181CrossRefPubMedGoogle Scholar
  14. 14.
    Eklind, K. I., Morse, M. A., Chung, F. L. 1990Distribution and metabolism of the natural anticarcinogen phenethyl isothiocyanate in A/J miceCarcinogenesis1120332036PubMedGoogle Scholar
  15. 15.
    Adesida, A., Edwards, L. G., Thornalley, P. J. 1996Inhibition of human leukaemia 60 cell growth by mercapturic acid metabolites of phenylethyl isothiocyanateFood Chem. Toxicol.34385392CrossRefPubMedGoogle Scholar
  16. 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
  17. 17.
    Conaway, C. C., Jiao, D., Kohri, T., Liebes, L., Chung, F. L. 1999Disposition and pharmacokinetics of phenethyl isothiocyanate and 6-phenylhexyl isothiocyanate in F344 ratsDrug Metab. Dispos.271320PubMedGoogle Scholar
  18. 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
  19. 19.
    Tseng, E., Kamath, A., Morris, M. E. 2002Effect of organic isothiocyanates on the P-glycoprotein- and MRP1-mediated transport of daunomycin and vinblastinePharm. Res.1915091515CrossRefPubMedGoogle Scholar
  20. 20.
    Hu, K., Morris, E. 2004Effects of benzyl-, phenethyl-, and alpha-naphthyl isothiocyanates on P-glycoprotein- and MRP1-mediated transportJ. Pharm. Sci.9319011911CrossRefPubMedGoogle Scholar
  21. 21.
    Ji, Y., Morris, M. E. 2004Effect of organic isothiocyanates on breast cancer resistance protein (ABCG2)-mediated transportPharm. Res.2122612269CrossRefPubMedGoogle Scholar
  22. 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
  23. 23.
    Schinkel, A. H., Jonker, J. W. 2003Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overviewAdv. Drug Deliv. Rev.55329CrossRefPubMedGoogle Scholar
  24. 24.
    Mullin, W. J. 1978High-performance liquid chromatography and gas chromatography of organic isothiocyanates and their methanol–isothiocyanate addition compoundsJ. Chromatogr.155198202CrossRefGoogle Scholar
  25. 25.
    Ji, Y., Morris, M. E. 2003Determination of phenethyl isothiocyanate in human plasma and urine by ammonia derivatization and liquid chromatography–tandem mass spectrometryAnal. Biochem.3233947CrossRefPubMedGoogle Scholar
  26. 26.
    Tookey, H. L., Etten, C. H., Daxenbichler, M. E 1980GlucosinolatesLiener, I. E. eds. Toxic Constituents of Plant Foodstuffs2Academic PressNew York103142Chap. 4Google Scholar
  27. 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
  28. 28.
    Callaway, E. C., Zhang, Y., Chew, W., Chow, H. H. 2004Cellular accumulation of dietary anticarcinogenic isothiocyanates is followed by transporter-mediated export as dithiocarbamatesCancer Lett.2042331CrossRefPubMedGoogle Scholar
  29. 29.
    Cole, S. P., Bhardwaj, G., Gerlach, J. H., Mackie, J. E., Grant, C. E., Almquist, K. C., Stewart, A. J., Kurz, E. U., Duncan, A. M., Deeley, R. G. 1992Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell lineScience25816501654PubMedGoogle Scholar
  30. 30.
    Borst, P., Evers, R., Kool, M., Wijnholds, J. 2000A family of drug transporters: the multidrug resistance-associated proteinsJ. Natl. Cancer Inst.9212951302CrossRefPubMedGoogle Scholar
  31. 31.
    Xu, K., Thornalley, P. J. 2001Involvement of glutathione metabolism in the cytotoxicity of the phenethyl isothiocyanate and its cysteine conjugate to human leukaemia cells in vitroBiochem. Pharmacol.61165177CrossRefPubMedGoogle Scholar
  32. 32.
    Zhang, Y., Kolm, R. H., Mannervik, B., Talalay, P. 1995Reversible conjugation of isothiocyanates with glutathione catalyzed by human glutathione transferasesBiochem. Biophys. Res. Commun.206748755CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical SciencesUniversity at Buffalo, State University of New York at BuffaloAmherstUSA
  2. 2.Merck & Co., Inc.West PointUSA

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