Pharmacokinetics of Cajaninstilbene Acid and Its Main Glucuronide Metabolite in Rats

Abstract

As a major active stilbene from the leaves of pigeon pea (Cajanus cajan), cajaninstilbene acid (CSA) exerts various pharmacological activities. The present study aimed to investigate the pharmacokinetics of CSA and one of its main metabolites (M1) to explore their fate in the body and provide a pharmacokinetic foundation for their in vivo biological activities and functional food or complementary medicine application. M1 was characterized as CSA-3-O-glucuronide using the multiple reaction monitoring-information-dependent acquisition-enhanced product ion technique. After oral and intravenous administration, plasma, urine, and bile were collected and analyzed to estimate pharmacokinetic properties of CSA and M1 and to explore the main excretion route. The oral bioavailability of CSA was estimated to be 44.36%. This study first reported that CSA is mainly metabolized to CSA-3-O-glucuronide via the first-pass effect to limit its oral bioavailability and excreted predominantly through the biliary route, while the enterohepatic circulation, extravascular distribution, and renal reabsorption characteristics of CSA might delay its elimination.

Absorption, Metabolism, and Excretion of Cajaninstilbene Acid

“…Total ion, total wavelength, and extracted ion chromatograms are shown in Figures 1 and 2. Comparing these chromatograms of dosing samples with blank samples, M1 12 and four new metabolites (M2−M5) of CSA were detected. MS/MS product ion mass data (Figure 3A and Table 3) are used to identify the mass fragmentation pathways of CSA and M1−M5 (Figures S4−S7).…”

“…Table 4 shows the biliary and urinary excretion of CSA metabolites M1, which was determined in our previous study, 12 as well as M2−M5 in rats after intravenous administration of CSA (2 mg/kg). M1−M5 were excreted from bile with 24.91, 8.48, 8.94, 19.67, and 15.35% and from urine with 1.03, 0.14, 0.86, 1.67, and 0.18% of the CSA dose over 0−24 h post dosing, respectively.…”

“…Based on the conditions in our previous study, the metabolites of CSA were identified by HPLC-DAD-QTRAP MS/MS detection, which was performed using multiple reaction monitoring-information-dependent acquisition-enhanced product ion (MRM-IDA-EPI) measurements. 12 UPLC-Q-TOF-MS detection was conducted using a Q-TOF SYNAPT mass spectrometer equipped with an Acquity UPLC system (Waters Corporation, Milford, MA). Chromatographic separation was achieved on a Thermo Syncronis C 18 column (50 × 2.1 mm 2 , 1.7 μm) kept at 35 °C.…”

“…The preparation and measurement of bile and urine samples were performed according to the method in our previous study. 12 The molar concentrations of CSA metabolites were calculated by CSA standard curves since they have similar molar extinction coefficients. 19 The excretion extent was expressed as the percentage of excreted amount relative to the amount of CSA administered.…”

“…11 Later, our group identified a main in vivo metabolite of CSA in the plasma, CSA-3-O-glucuronide, and explored the oral bioavailability and excretion routes of CSA. 12 Based on this result, we developed uridine 5′-diphosphate (UDP)-glucuronosyltransferase, an inhibitory excipient containing a selfmicroemulsion delivery system, to reduce the production of CSA glucuronide metabolites, which can increase CSA oral bioavailability. 13 However, the absorption mechanism and detailed metabolic pathways of CSA as well as the excretion routes of its metabolites have not been clarified so far.…”