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Pharmacokinetics of Dietary Phenethyl Isothiocyanate in Rats

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Purpose

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°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.

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°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.

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.

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Abbreviations

AUC:

area under the plasma concentration vs. time curve

BCRP:

breast cancer resistance protein

C max :

maximal plasma concentration

Cl:

clearance

F :

bioavailability

f u :

the unbound fraction

ITC:

isothiocyanate

i.v.:

intravenous

k a :

absorption rate constant

k d :

degradation rate constant

MRP:

multidrug resistance-associated protein

PEITC:

phenethyl isothiocyanate

PEITC-SG:

glutathione conjugate of PEITC

RT:

room temperature

t max :

time to reach Cmax

t 1/2 :

elimination half-life

t 1/2,d :

degradation half-life

V ss :

volume of distribution

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Acknowledgments

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.

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Authors and Affiliations

  1. 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

    Yan Ji & Marilyn E. Morris

  2. Merck & Co., Inc., WP75-100, PO Box 4, West Point, Pennsylvania, 19486, USA

    Yuhsin Kuo

Authors
  1. Yan Ji
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  3. Marilyn E. Morris
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Correspondence to Marilyn E. Morris.

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Ji, Y., Kuo, Y. & Morris, M.E. Pharmacokinetics of Dietary Phenethyl Isothiocyanate in Rats. Pharm Res 22, 1658–1666 (2005). https://doi.org/10.1007/s11095-005-7097-z

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