Pre-clinical Pharmacokinetic and Metabolomic Analyses of Isorhapontigenin, a Dietary Resveratrol Derivative

Abstract

Background: Isorhapontigenin (trans-3,5,4'-trihydroxy-3'-methoxystilbene, ISO), a dietary resveratrol (trans-3,5,4'-trihydroxystilbene) derivative, possesses various health-promoting activities. To further evaluate its medicinal potentials, the pharmacokinetic and metabolomic profiles of ISO were examined in Sprague-Dawley rats. Methods: The plasma pharmacokinetics and metabolomics were monitored by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS), respectively. Results: Upon intravenous injection (90 μmol/kg), ISO exhibited a fairly rapid clearance (CL) and short mean residence time (MRT). After a single oral administration (100 μmol/kg), ISO was rapidly absorbed and showed a long residence in the systemic circulation. Dose escalation to 200 μmol/kg resulted in higher dose-normalized maximal plasma concentrations (C_max/Dose), dose-normalized plasma exposures (AUC/Dose), and oral bioavailability (F). One-week repeated daily dosing of ISO did not alter its major oral pharmacokinetic parameters. Pharmacokinetic comparisons clearly indicated that ISO displayed pharmacokinetic profiles superior to resveratrol as its C_max/Dose, AUC/Dose, and F were approximately two to three folds greater than resveratrol. Metabolomic investigation revealed that 1-week ISO administration significantly reduced plasma concentrations of arachidonic acid, cholesterol, fructose, allantoin, and cadaverine but increased tryptamine levels, indicating its impact on metabolic pathways related to health-promoting effects. Conclusion: ISO displayed favorable pharmacokinetic profiles and may be a promising nutraceutical in view of its health-promoting properties.

Keywords: isorhapontigenin; metabolomics; oral bioavailability; pharmacokinetics; resveratrol.

FIGURE 1

Chemical structures of resveratrol (A) and isorhapontigenin (B).

FIGURE 2

MS/MS spectra of isorhapontigenin and proposed fragmentation pattern of m/z 257.2 → 241.1 transition.

FIGURE 3

Typical MRM chromatograms of (A) a pre-dosing plasma sample; (B) a blank plasma sample spiked with 3 ng/mL isorhapontigenin; (C) a blank plasma sample spiked with 30 ng/mL internal standard; (D) a plasma sample collected 90 min after intravenous injection; and (E) a plasma sample collected 180 min after oral dosing. Red: MRM precursor-to-product ion transition of m/z 257.2 → 241.1 and blue: MRM precursor-to-product ion transition of m/z 241.0 → 181.0. Peak 1, isorhapontigenin; peak 2, internal standard; and peaks 3, unidentified metabolite.

FIGURE 4

Pharmacokinetics of isorhapontigenin. Plasma isorhapontigenin levels were measured with LC–MS/MS. Symbols represent mean concentrations and error bars represent SD. (A) Groups 1 – 3: n = 5; except Group 2 at 720 min where n = 4. (B) Group 4: n = 7.

FIGURE 5

Pharmacokinetic comparison between isorhapontigenin and resveratrol. The pharmacokinetic data of resveratrol was extracted from a previous report with permission (Data Reuse License Number: 4282330274888). ISO, isorhapontigenin; RES, resveratrol. Symbols represent mean values, while error bars represent SD.

FIGURE 6

Metabolomics of isorhapontigenin. (A) Results of PLS-DA. Green •: rats received 1-week ISO intervention and blue •: rats received vehicle. (B) Results of permutation test. Green •: R² (goodness-of-fit parameter) and blue ■: Q² (goodness-of-prediction parameter). (C): Fold change heatmap of plasma metabolites altered by 1-week ISO intervention.