Pharmaceutical Research

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

Pharmacokinetics of Dietary Phenethyl Isothiocyanate in Rats

Research Paper

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.

Key Words

bioavailability PEITC pharmacokinetics phenethyl isothiocyanate protein binding rats stability 

Abbreviations

AUC

area under the plasma concentration vs. time curve

BCRP

breast cancer resistance protein

Cmax

maximal plasma concentration

Cl

clearance

F

bioavailability

fu

the unbound fraction

ITC

isothiocyanate

i.v.

intravenous

ka

absorption rate constant

kd

degradation rate constant

MRP

multidrug resistance-associated protein

PEITC

phenethyl isothiocyanate

PEITC-SG

glutathione conjugate of PEITC

RT

room temperature

tmax

time to reach Cmax

t1/2

elimination half-life

t1/2,d

degradation half-life

Vss

volume of distribution

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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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