Absolute bioavailability and dose-dependent pharmacokinetic behaviour of dietary doses of the chemopreventive isothiocyanate sulforaphane in rat

Abstract

Sulforaphane is a naturally occurring isothiocyanate with promising chemopreventive activity. An analytical method, utilising liquid chromatography-MS/MS, which allows the determination of sulforaphane in small volumes of rat plasma following exposure to low dietary doses, was developed and validated, and employed to determine its absolute bioavailability and pharmacokinetic characteristics. Rats were treated with either a single intravenous dose of sulforaphane (2·8 mmol/kg) or single oral doses of 2·8, 5·6 and 28 mmol/kg. Sulforaphane plasma concentrations were determined in blood samples withdrawn from the rat tail at regular time intervals. Following intravenous administration, the plasma profile of sulforaphane was best described by a two-compartment pharmacokinetic model, with a prolonged terminal phase. Sulforaphane was very well and rapidly absorbed and displayed an absolute bioavailability of 82 %, which, however, decreased at the higher doses, indicating a dose-dependent pharmacokinetic behaviour; similarly, C max values did not rise proportionately to the dose. At the highest dose used, the rate of absorption constant k ab , biological half-life t1 2 and apparent volume of distribution decreased significantly. It is concluded that in the rat orally administered sulforaphane is rapidly absorbed, achieving high absolute bioavailability at low dietary doses, but dose-dependent pharmacokinetics was evident, with bioavailability decreasing with increasing dose.

Modulation of rat pulmonary carcinogen-metabolising enzyme systems by the isothiocyanates erucin and sulforaphane

“…As exemplified by the leakage of lactate dehydrogenase, erucin appears to be less toxic than sulforaphane to rat lung slices. It should be emphasised that such concentrations are unlikely to be achieved following single dietary intake of these isothiocyanates; when rats were treated with a single dose of sulforaphane, simulating human intake, the maximum plasma concentrations achieved were <0.3 μM [38]. However, plasma concentrations of isothiocyanates are likely to be higher in individuals consuming cruciferous vegetables daily or take nutritional supplements of isothiocyanates.…”

The naturally occurring aliphatic isothiocyanates sulforaphane and erucin are weak agonists but potent non-competitive antagonists of the aryl hydrocarbon receptor

“…When the vegetable is disrupted, such as during mastication, the enzyme myrosinase (β-thioglucoside glucohydrolase) comes into contact with the glucosinolate converting it to the isothiocyanate; similar conversion takes place in the human intestine by virtue of microbial myrosinase (Verkerk et al 2009). Isothiocyanates such as sulforaphane are very well absorbed and achieve high bioavailability in both rat and human (Hanlon et al 2008a(Hanlon et al , 2009a. A number of studies in chemically-induced models of cancer have established that sulforaphane and other isothiocyanates are potent anticarcinogens (Kuroiwa et al 2006;Hecht 2000).…”

Hill coefficients of dietary polyphenolic enzyme inhibitiors: can beneficial health effects of dietary polyphenols be explained by allosteric enzyme denaturing?

“…To estimate the relative value of these two alternatives, we would like to argue as follows: in order for any compound to show a physiologically relevant biological effect by single site inhibition, the blood plasma concentration of the compound must reach a level equivalent to its inhibition constant IC 50 [41]. This notion is undisputed, constituting a key element in pharmaceutical chemistry.…”

“…In particular, plants in groups 2 and 3 seem to follow a cunning strategy by producing a vast number of structurally diverse polyphenolic compounds (e.g., at least 30,000 in the case of the thearubigins in tea Camellia sinensis) each in small quantities (femtomolar to nanomolar), quantities too small to show even after significant absorption any biological effect that could be rationalized in terms of single active site enzyme inhibition [41,55]. However, if one assumes that these compounds are produced with a single aim of nonspecific allosteric enzyme denaturation by the insect swarm hypothesis, this plot of nature suddenly seems to make sense.…”