Comparison of Pharmacokinetics and Anti-Pulmonary Fibrosis-Related Effects of Sulforaphane and Sulforaphane N-acetylcysteine

Abstract

Sulforaphane (SFN), belonging to the isothiocyanate family, has received attention owing to its beneficial activities, including chemopreventive and antifibrotic effects. As sulforaphane N-acetylcysteine (SFN-NAC), a major sulforaphane metabolite, has presented similar pharmacological activities to those of SFN, it is crucial to simultaneously analyze the pharmacokinetics and activities of SFN and SFN-NAC, to comprehensively elucidate the efficacy of SFN-containing products. Accordingly, the anti-pulmonary fibrotic effects of SFN and SFN-NAC were assessed, with simultaneous evaluation of permeability, metabolic stability, and in vivo pharmacokinetics. Both SFN and SFN-NAC decreased the levels of transforming growth factor-β1-induced fibronectin, alpha-smooth muscle actin, and collagen, which are major mediators of fibrosis, in MRC-5 fibroblast cells. Regarding pharmacokinetics, SFN and SFN-NAC were metabolically unstable, especially in the plasma. SFN-NAC degraded considerably faster than SFN in plasma, with SFN being formed from SFN-NAC. In rats, SFN and SFN-NAC showed a similar clearance when administered intravenously; however, SFN showed markedly superior absorption when administered orally. Although the plasma SFN-NAC concentration was low owing to poor absorption following oral administration, SFN-NAC was converted to SFN in vivo, as in plasma. Collectively, these data suggest that SFN-NAC could benefit a prodrug formulation strategy, possibly avoiding the gastrointestinal side effects of SFN, and with improved SFN-NAC absorption.

Sulforaphane attenuates glycoprotein VI-mediated platelet mitochondrial dysfunction through up-regulating the cAMP/PKA signaling pathway in vitro and in vivo

“…16 With a terminal half-life ranging between 42 min and 65.6 h in rats, SFN is ultimately conjugated with glutathione and further metabolized through the mercapturic acid pathway and excreted through the renal route. 47,50 Our present in vivo study showed that the plasma concentration of SFN was 0.124 μM after 12 weeks of BSE supplementation at a dose of 600 mg kg −1 diet, which is consistent with another report. 51 Nevertheless, the concentrations of SFN used in our in vitro study ranged from 1 μM to 10 μM, and the significant inhibitory effects were mainly observed at 5 μM and 10 μM.…”

“…Studies have suggested that SFN is well absorbed in the intestine with oral bioavailability over 70% in rats. 46,47 Serum/plasma concentrations of free SFN largely depend on many factors, e.g. , the amount of GSL, myrosinases, and SFN in cruciferous vegetables (that mainly depends on the maturity rate and processing technology), gut flora, as well as the time points of testing after administration.…”

“…Studies have suggested that SFN is well absorbed in the intestine with oral bioavailability over 70% in rats. 46,47 Serum/plasma concentrations of free SFN largely depend on many factors, e.g., the amount of GSL, myrosinases, and SFN in cruciferous vegetables (that mainly depends on the maturity rate and processing technology), gut flora, as well as the time points of testing after administration. 47 It has been shown that the maximal plasma SFN concentration in rats can be reached 15.2 μM at 1.5 h after a single oral dose of SFN at 150 μM per kg body weight 48 and 20 μM at 4 h after a single oral dose of 50 μM SFN.…”

“…46,47 Serum/plasma concentrations of free SFN largely depend on many factors, e.g., the amount of GSL, myrosinases, and SFN in cruciferous vegetables (that mainly depends on the maturity rate and processing technology), gut flora, as well as the time points of testing after administration. 47 It has been shown that the maximal plasma SFN concentration in rats can be reached 15.2 μM at 1.5 h after a single oral dose of SFN at 150 μM per kg body weight 48 and 20 μM at 4 h after a single oral dose of 50 μM SFN. 49 In general, clinical trials have reported that the plasma peak concentration of SFN in volunteers is below 7.4 μM at 1-4 h post-consumption of broccoli sprouts, raw or cooked broccolis, or high-glucosino-Food & Function Paper late broccolis.…”

Bioavailable Sulforaphane Quantitation in Plasma by LC–MS/MS Is Enhanced by Blocking Thiols

“…Recently, SFN-NAC was shown to readily convert to SFN in rats when administered orally and in plasma, and both had similar antipulmonary fibrotic effects. 11 In summary, SFN metabolites are readily reversible and yield free, bioavailable SFN.…”