peoniflorin and sinomenine

An accurate and reliable high-performance liquid chromatography-diode array detector (HPLC-DAD) method was developed and validated for determination of sinomenine (SI), paeoniflorin (PF) and paeonol (PA), which was further applied to assess the pharmacokinetics of SI, PF and PA in an anti-arthritic herbal product, Qingfu Guanjieshu (QFGJS) capsule, in rats. Successful separation was achieved with a C18 column and a mobile phase composed of acetonitrile and aqueous phase (containing 0.1% formic acid, adjusted with triethylamine to pH 3.5 ± 0.2). The method was validated with excellent precision, accuracy, recovery and stability in calibration ranges from 0.06 to 11.62 µg/mL for SI, from 0.09 to 35.70 µg/mL for PF, and from 0.15 to 4.53 µg/mL for PA (with r(2) > 0.999 for all three compounds). Our results showed that absorption of PF after administration of QFGJS was similar to that after oral administration of PF alone; the absorption of SI was decreased while the absorption of PA was increased after giving QFGJS orally compared with pure compounds. We may conclude that pharmacokinetic studies of complex herbal products are not only necessary but also feasible by using representative bioactive chemicals as indicators of establishing quality control standards and of determining pharmacokinetic behavior of herbal medicines.

Topics: Acetophenones; Administration, Oral; Animals; Chromatography, High Pressure Liquid; Drug Stability; Drugs, Chinese Herbal; Glucosides; Linear Models; Male; Monoterpenes; Morphinans; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity

Paeoniflorin and sinomenine, derived from the root of Paeonia lactiflora Pall. (family Ranunculaceae) and the stem of Sinomenium acutum Rehder & Wilson (family Menispermaceae), respectively, have been, and are currently, widely used for treatment of rheumatic and arthritic diseases in China and Japan. Our previous studies demonstrated that sinomenine could significantly improve the bioavailability of paeoniflorin in rats, but the underlying mechanisms remain unknown. The present study aims to investigate the intestinal kinetic absorptive characteristics of paeoniflorin as well as the absorptive behavior influenced by co-administration of sinomenine using an in vitro everted rat gut sac model. The results showed a good linear correlation between the paeoniflorin absorption in sac contents and the incubation time from 0 to 90 min. However, the concentration dependence showed that a non-linear correlation exists between the paeoniflorin absorption and its concentrations from 10 to 160 microM, and the absorption was saturated at about 80 microM of the drug. Sinomenine at 16 and 136 microM concentrations could significantly enhance the absorption of paeoniflorin (20 microM) by 1.5- and 2.5-fold, respectively. Moreover, two well-known P-glycoprotein inhibitors, verapamil and quinidine, could significantly elevate the absorption of paeoniflorin by 2.1- and 1.5-fold, respectively. Furthermore, sinomenine in a pattern, which influenced paeoniflorin's absorption, manifested as similar to that of P-glycoprotein inhibitors. In conclusion, sinomenine significantly enhance the intestinal absorption of paeoniflorin, subsequently improve the bioavailability of paeoniflorin. The mechanism underlying the improvement of paeoniflorin's bioavailability was proposed that sinomenine could decrease the efflux transport of paeoniflorin by P-glycoprotein.

Topics: Animals; Anti-Inflammatory Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzoates; Bridged-Ring Compounds; Digoxin; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Glucosides; In Vitro Techniques; Intestinal Absorption; Intestinal Mucosa; Intestines; Male; Models, Animal; Monoterpenes; Morphinans; Paeonia; Quinidine; Rats; Rats, Sprague-Dawley; Sinomenium; Time Factors; Verapamil

To determine the intestinal disposition mechanisms of paeoniflorin, a bioactive glucoside, and to investigate the mechanisms by which sinomenine increases paeoniflorin bioavailability.. A single-pass "four-site" rat intestinal perfusion model and a cultured Caco-2 cell model were employed.. In both model systems, paeoniflorin permeability was poor. In the perfusion model, maximal absorption and metabolism of paeoniflorin occurred in duodenum and jejunum, which were significantly decreased by a glucosidase inhibitor gluconolactone (20 mM). On the other hand, paeoniflorin absorption in terminal ileum increased significantly but its metabolism did not in the presence of sinomenine and cyclosporine A. In the Caco-2 cell model, paeoniflorin was transported 48-fold slower than its aglycone (paeoniflorigenin). Absorptive transport of paeoniflorin was significantly (p < 0.05) increased by sinomenine (38%), verapamil (27%), and cyclosporine A (41%), whereas its secretory transport was significantly (p < 0.01) decreased by sinomenine (50%), verapamil (35%) and cyclosporine A (37%). In contrast, MRP inhibitors MK-571 and leukotriene C4 did not affect transport of paeoniflorin. Lastly, sinomenine was also shown to significantly increase the absorptive transport of digoxin (a prototypical p-glycoprotein substrate) and to significantly decrease its secretory transport.. Poor permeation, p-gp-mediated efflux, and hydrolysis via a glucosidase contributed to the poor bioavailability of paeoniflorin. Sinomenine (an inhibitor of the p-gp-mediated digoxin efflux) increased paeoniflorin's bioavailability via the inhibition of p-gp-mediated paeoniflorin efflux in the intestine.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Benzoates; Biological Availability; Biological Transport; Bridged-Ring Compounds; Caco-2 Cells; Cells, Cultured; Chromatography, High Pressure Liquid; Digoxin; Drug Interactions; Glucosides; Humans; Intestinal Absorption; Male; Monoterpenes; Morphinans; Rats; Rats, Sprague-Dawley

Paeonia lactiflora Pall. (Ranunculaceae) root and Sinomenium acutum Rehder and Wilson (Menispermaceae) stem are two herbs widely used in Chinese medicine to treat rheumatoid arthritis. While, in theory, either herb could be used alone, in practice, Chinese medicine practitioners prescribe them together. Studies on pharmacokinetic interaction between the active constituents of these two herbs (paeoniflorin and sinomenine, respectively) provide empirical evidence to support their clinical practice. A single dose of paeoniflorin (150 mg/kg) alone and with sinomenine hydrochloride (90 mg/kg) was administered by gastric gavage to unrestrained conscious male Sprague-Dawley rats (n=5 or 6, 240-270 [corrected] g). Blood samples were collected periodically via a jugular vein before and after dosing from 10 min to 12 h. A high-performance liquid chromatographic (HPLC) assay was developed to determine the plasma concentrations of paeoniflorin. Non-compartmental pharmacokinetic profiles were constructed by using the software PK Solutions 2.0. The pharmacokinetic parameters were compared using unpaired Student t-test. After co-administration of sinomenine, the peak plasma concentration of paeoniflorin was elevated (P<0.01), the peak time was delayed (P<0.01), the AUC(0-t) was increased (P<0.001), the mean residence time (MRT) was prolonged (P<0.01), the C(L) was decreased (P<0.01) and the V(d) was reduced (P<0.05). These results indicate that sinomenine hydrochloride at 90 mg/kg significantly improved the bioavailability of paeoniflorin in rats.

Topics: Animals; Area Under Curve; Benzoates; Biological Availability; Bridged-Ring Compounds; Calibration; Chromatography, High Pressure Liquid; Glucosides; Half-Life; Male; Monoterpenes; Morphinans; Rats; Rats, Sprague-Dawley; Reproducibility of Results

The root of Paeonia lactiflora and the stem of Sinomenium acutum are two herbs widely used in Chinese herbal medicine for the treatment of inflammatory and arthritic diseases. Studies on the interaction of the active constituents of these herbs, i.e., paeoniflorin and sinomenine, in pharmacokinetic parameters, tissues distribution, and protein binding ability could provide empirical data to support their clinical application. Following oral administration to rats, the pharmacokinetic alterations were compared. The results showed that the pharmacokinetic parameters (Cmax, Tmax, AUC, MRT, C(L), and Vd) of paeoniflorin were markedly enhanced when co-administrated with sinomenine. At 45 min after oral administration, the concentrations of paeoniflorin in the main internal organs were significantly increased when co-administrated with sinomenine. These phenomena were not ascribable to the alteration of the protein binding ability of paeoniflorin by sinomenine because obvious interactions of paeoniflorin and sinomenine in protein binding abilities in vitro to rat and rabbit plasma, human albumin, and alpha-1-acid-glycoprotein were not observed. However, with respect to the in vivo influence of paeoniflorin on sinomenine, the results showed that co-administration of paeoniflorin did not affect the pharmacokinetic parameters and tissue distribution of sinomenine.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Benzoates; Bridged-Ring Compounds; Chromatography, High Pressure Liquid; Dialysis; Drug Interactions; Glucosides; Male; Monoterpenes; Morphinans; Protein Binding; Rats; Rats, Sprague-Dawley; Reference Standards; Reproducibility of Results; Tissue Distribution