Pharmacokinetics Of Paeoniflorin Research Articles

Comparative Study on the Pharmacokinetics of Paeoniflorin, White Peony Root Water Extract, and Taohong Siwu Decoction After Oral Administration in Rats

Taohong Siwu Decoction (TSD) is a classic traditional Chinese medicine (TCM) compound with pharmacological effects such as vasodilation and hypolipidemia. Paeoniflorin (PF) is one of the active ingredients of TSD. The aim of this study was to evaluate the pharmacokinetics of PF in herbal extracts and their purified formsin rats. A sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) method for the determination of PF in rat plasma was developed. Rats were divided into three groups, and given PF solution, water extract of white peony root (WPR), or TSD by gavage. At different predetermined timepoints after gavage, blood was collected from the orbital vein. The pharmacokinetic parameters of PF in the plasma of rats in the three groups was determined. The pharmacokinetic studies showed that the time to reach maximum concentration (Tmax) of PF in the purified forms group was relatively high, while the half-lives (T½) of PF in the TSD and WPR groups were longer. Among the three groups, PF in the purified forms group had the maximum area under the concentration-time curve (AUC0-t=732.997µg/L·h) and the largest maximum concentration (Cmax=313.460µg/L), which showed a significant difference compared with the TSD group (P<0.05). Compared with the purified group, the clearance (CLz/F=86.004L/h/kg) and the apparent volume of distribution (Vz/F=254.787L/kg) of PF in the TSD group increased significantly (P<0.05). A highly specific, sensitive, and rapid HPLC-MS-MS method was developed and applied for the determination of PF in rat plasma. It was found that TSD and WPR can prolong the action time of paeoniflorin in the body.

Effects of glycyrrhizin on the pharmacokinetics of paeoniflorin in rats and its potential mechanism

Context: Paeoniflorin is reported to possess numerous pharmacological activities. Paeoniflorin and glycyrrhizin are always used together for the treatment of disease in China clinics; however, the drug–drug interaction between glycyrrhizin and paeoniflorin is still unknown.Objective: This study investigates the effects of glycyrrhizin on the pharmacokinetics of paeoniflorin in rats.Materials and methods: The pharmacokinetics of orally administered paeoniflorin (20 mg/kg) with or without glycyrrhizin pre-treatment (at a dose of 100 mg/kg/day for 7 days) were investigated in male Sprague–Dawley rats using LC-MS/MS. Additionally, Caco-2 cell transwell model and rat liver microsome incubation experiments were also conducted to investigate its potential mechanism.Results: The results showed that when the rats were pre-treated with glycyrrhizin, the Cmax of paeoniflorin decreased from 59.57 ± 10.24 to 45.36 ± 8.61 ng/mL, and AUC0-inf also decreased from 282.02 ± 35.06 to 202.29 ± 28.28 μg·h/L. The t1/2 value of paeoniflorin decreased from 8.48 ± 2.01 to 5.88 ± 1.15 h (p < 0.05). The Caco-2 cell transwell experiments indicated that glycyrrhizin could increase the efflux ratio of paeoniflorin from 2.71 to 3.52, and the rat liver microsome incubation experiments showed that glycyrrhizin could significantly increase its intrinsic clearance rate from 53.7 ± 4.6 to 85.6 ± 7.1 μL/min/mg protein.Conclusions: These results indicated that glycyrrhizin could affect the pharmacokinetics of paeoniflorin, and it might work through decreasing the absorption of paeoniflorin by inducing the activity of P-gp or through increasing the clearance rate in rat liver by inducing the activity of CYP450 enzyme.

Erratum for: A Sensitive and Specific Indirect Competitive Enzyme-Linked Immunosorbent Assay for Detection of Paeoniflorin and Its Application in Pharmacokinetic Interactions between Paeoniflorin and Glycyrrhizinic Acid.

This study aimed to develop an indirect competitive enzyme-linked immunosorbent assay based on monoclonal antibodies against paeoniflorin to study the effects of different doses of glycyrrhizinic acid on the pharmacokinetics of paeoniflorin in mice. An anti-paeoniflorin monoclonal antibody was produced from a hybridoma created through a fusion of splenocytes immunized with paeoniflorin-bovine serum albumin and conjugated with the hypoxanthine-aminopterin-thymidine-sensitive mouse myeloma cell line SP2/0. The resultant antibody was used to develop and validate a rapid, specific and sensitive, indirect competitive enzyme-linked immunosorbent assay for the measurement of paeoniflorin (linear range 4.8–312.5 ng · mL−1). The intraday and interday precision values of the indirect competitive ELISA method were well within the recommended range (≤ 10 %), and the recovery rate was, on average, 101.13 %. Pharmacokinetic parameters obtained from mouse blood samples at various intervals following the oral administration of paeoniflorin and glycyrrhizic acid at three doses (1 : 0.3, 1 : 1, 1 : 3, respectively) demonstrated that the highest dose of glycyrrhizic acid inhibits the absorption of paeoniflorin.

A Sensitive and Specific Indirect Competitive Enzyme-Linked Immunosorbent Assay for Detection of Paeoniflorin and Its Application in Pharmacokinetic Interactions between Paeoniflorin and Glycyrrhizinic Acid.

This study aimed to develop an indirect competitive enzyme-linked immunosorbent assay based on monoclonal antibodies against paeoniflorin to study the effects of different doses of glycyrrhizinic acid on the pharmacokinetics of paeoniflorin in mice. An anti-paeoniflorin monoclonal antibody was produced from a hybridoma created through a fusion of splenocytes immunized with paeoniflorin-bovine serum albumin and conjugated with the hypoxanthine-aminopterin-thymidine-sensitive mouse myeloma cell line SP2/0. The resultant antibody was used to develop and validate a rapid, specific and sensitive, indirect competitive enzyme-linked immunosorbent assay for the measurement of paeoniflorin (linear range 4.8-312.5 ng · mL(-1)). The intraday and interday precision values of the indirect competitive ELISA method were well within the recommended range (≤ 10 %), and the recovery rate was, on average, 101.13 %. Pharmacokinetic parameters obtained from mouse blood samples at various intervals following the oral administration of paeoniflorin and glycyrrhizic acid at three doses (1 : 0.3, 1 : 1, 1 : 3, respectively) demonstrated that the highest dose of glycyrrhizic acid inhibits the absorption of paeoniflorin.

Influence of co-administered antibiotics on the pharmacokinetic fate in rats of paeoniflorin and its active metabolite paeonimetabolin-I from Shaoyao-Gancao-tang.

The effects of orally co-administered antibiotics on the pharmacokinetics of paeoniflorin (PF) and paeonimetabolin-I (PM-I), a bioactive metabolite derived from PF by intestinal bacteria, from the traditional Chinese formulation, Shaoyao-Gancao-tang (SGT), were investigated in rats to clarify the effect of administering SGT together with some synthetic drugs. Co-administration of the antibiotics amoxicillin and metronidazole (AMPC-MET) significantly increased the area under the plasma concentration versus time curve (AUC) of PF, whereas it markedly decreased that of PM-I, to 2.6% of the normal AUC by administration of a single dose, and less than 1% by a 3-day pretreatment. Similar effects were observed using the combination of ofloxacin with SGT. The PF-metabolizing activity of intestinal bacteria was reduced to 16% and 33% of normal levels by treatment with AMPC-MET and ofloxacin, respectively, which caused alterations of that degree in the extent of absorption of PF and PM-I, but did not affect their rate of absorption or elimination. The present study suggests that it may not be appropriate to use SGT simultaneously with antibiotics such as AMPC-MET or ofloxacin, and also reveals the important role of intestinal bacteria in the pharmacokinetics of the active components of this traditional Chinese formulation.

Effects of cerebral ischemia-reperfusion on pharmacokinetic fate of paeoniflorin after intravenous administration of Paeoniae Radix extract in rats

The objective of the present study was to investigate the effects of cerebral ischemia-reperfusion on pharmacokinetics of paeoniflorin after intravenous administration of Paeoniae Radix extract (PRE) in rats. The cerebral ischemia-reperfusion rats were induced by occluding the bilateral carotid arteries of normal rats for 2 h, followed by reperfusion. The resultant animals were immediately administrated by PRE (at a dose of 60 mg/kg of paeoniflorin) via the femoral vein, whilst the same dose was injected to the normal rats. Plasma samples were collected at different time to construct pharmacokinetic profiles by plotting drug concentration versus time. Quantification of paeoniflorin in rat plasma was achieved by using a simple and rapid high-performance liquid chromatographic method. In normal rats, the major parameters of distribution half-life ( t 1/2α), elimination half-life ( t 1/2β), area under the plasma concentration–time (AUC), mean retention time (MRT), and clearance (CL), estimated by an open two-compartmental model, were 0.69, 18.77 min, 5338.71 (μg min)/ml, 18.13 min and 0.0162 mg/(kg min), respectively. However, in ischemia-reperfusion rats, the corresponding parameters were 2.04, 24.51 min, 9626.00 (μg min)/ml, 29.75 min and 0.0071 mg/(kg min), respectively. The results showed that ischemia- reperfusion significantly increased AUC values, decreased CL values, and prolonged the terminal half-life of paeoniflorin. These findings suggest that the injuries of ischemia-reperfusion could play an important role in pharmacokinetic process of paeoniflorin.

A deglucosylated metabolite of paeoniflorin of the root of Paeonia lactiflora and its pharmacokinetics in rats.

Paeoniflorin is a bioactive monoterpene glucoside in Paeoniae Radix (PR), the roots of Paeonia lactiflora (Ranunculaceae). By oral administration to rats with the decoction of PR, the metabolism and pharmacokinetics of paeoniflorin were investigated in this study. A deglucosylated metabolite of paeoniflorin, paeoniflorgenin (PG), in serum was identified based on HPLC/MS and NMR spectral data. HPLC/UV methods were developed for determining PG in serum and feces suspension. A non-compartment model was used for the calculation of pharmacokinetic parameters. Moreover, the metabolism of paeoniflorin by various types of feces was investigated as well. The paeoniflorin levels in serum were below the detection limit throughout the study. The C (max), t (max), and AUC (0-t) of PG were 8.0 microg/mL, 10 min and 487.0 microg min/mL, respectively. Paeoniflorin was found to be hydrolyzed into PG through incubation with feces of rabbit, rat, pig or human. Similar profiles of PG were shown for various types of feces, except for rabbit. In conclusion, paeoniflorin was not absorbed per se, whereas its aglycone paeoniflorgenin was absorbable and circulating in the bloodstream. Rat and pig are appropriate models for investigating the metabolism and pharmacokinetics of paeoniflorin.

Pharmacokinetics of Paeoniflorin After Oral Administration of Shao-yao Gan-chao Tang in Mice

Paeoniflorin, a monoterpene glycoside, is the principal bioactive component of Paeoniae Radix. The traditional prescription Shao-yao Gan-chao Tang (SGT; Kampo: Shakuyaku-Kanzo-To), which is composed of Paeoniae Radix and Glycyrrhizae Radix, has been widely used in China and Japan. Quantification of paeoniflorin in mouse plasma after oral administration of SGT (at a dose containing 10 mg/kg paeoniflorin) was achieved using a simple and rapid high-performance liquid chromatography method. The plasma concentration-time curves were fitted with mean terminal half-lives (t 1/2) of 116.17 min. The maximum plasma concentration (Cmax) of paeoniflorin was 111.56 ng/ml, time to reach maximum concentration (tmax) was 17.00 min, the area under the plasma concentration-time curve (AUC)0-t was 12293.42 ng x min/ml, clearance/bioavailability (CL/F) value was 644.74 ml/min x kg, apparent volume of distribution/ bioavailability (Vd/F) value was 103.05 l/kg, and the mean residence time (MRT) was 169.64 min. These results, together with the previously reported kinetic data of paeoniflorin after oral administration of Paeoniae Radix extract alone, indicated that absorption of paeoniflorin after oral administration of SGT was significantly greater than that after oral administration of Paeoniae Radix alone.

Dose-Dependent Pharmacokinetics of Paeoniflorin in Rats.

The pharmacokinetics of paeoniflorin (PAE) was examined after an iv dose of 20, 40, or 100mg/kg in rats. The decline of plasma concentration was biexponential after each dose. Dose, however, had a marked effect on the pharmacokinetics, with a greater than proportional increase in AUC at 100mg/ kg, even though the increase was proportional at the dose range from 20 to 40mg/kg. There was also significant decrease of the steady-state distribution volume (Vdss), and total body (CLtot), and renal (CLR) clearances at the high dose (p<0.01 or 0.05), without a significant difference between the two low doses. Plasma unbound fraction (0.75) was constant over the observed range of plasma PAE concentrations (0.8 ?? 700μg/ml). The decrease of Vdss was ascribed to the dose-dependent Kp values in liver, kidney, gastrointestinal tract, and skin. The significant decrease of biliary clearance (CLB) at 100mg/kg as compared with that at 20 and 40mg/kg contributed to the decrease of CLtot. It was suggested that the decreases of CLB and CLR may be a consequence of saturable transport from plasma into liver, and the significant decrease of glomerular filtration rate (p<0.05) at the higher steady-state plasma level than at the lower plasma levels might be owing to a decreasing effect of PAE on renal plasma flow, because transport from liver to bile did not appear to be saturable, and the excretion into urine seemed to occur only by glomerular filtration. Thus, the pharmacokinetics of PAE in rats was dosedependent.