Pharmacokinetic study of the prokinetic compounds meranzin hydrate and ferulic acid following oral administration of Chaihu-Shugan-San to patients with functional dyspepsia

Aim of the study

The prokinetic activity of ferulic acid derived from Ligusticum chuanxiong hort in the Chaihu-Shugan-San formula has been shown to be similar to Chaihu-Shugan-San, a popular traditional Chinese medicine for treating functional dyspepsia. The effects of meranzin hydrate, a compound isolated from Fructus aurantii in the Chaihu-Shugan-San formula, are unclear, as the pharmacokinetics have never been studied in patients with functional dyspepsia. This study aimed to describe the pharmacokinetics of ferulic acid and merazin hydrate by evaluating the prokinetics induced by Chaihu-Shugan-San and meranzin hydrate.

Materials and methods

Gastric emptying and intestinal transit were measured after oral administration of a single dose of Chaihu-Shugan-San or meranzin hydrate in rats. The tone of rat ileum was selected as direct evidence of the prokinetic activity of meranzin hydrate. Patients with functional dyspepsia were recruited, and meranzin hydrate and ferulic acid were identified by ultra performance liquid chromatography with tandem mass spectrometry in the plasma of patients following a single oral administration of Chaihu-Shugan-San. The resulting pharmacokinetic properties were determined by ultra performance liquid chromatography coupled to photo diode array.

Results

In rats, single doses of Chaihu-Shugan-San (20 g/kg) and meranzin hydrate (28 mg/kg) significantly accelerated gastric emptying and intestinal transit (Chaihu-Shugan-San: 68.9 ± 5.6% and 72.3 ± 4.7%, meranzin hydrate: 72.9 ± 3.8% and 75.2 ± 3.1%) compared with the control (55.45 ± 3.7% and 63.51 ± 5.1%, P < 0.05), showing similar results as cisapride (69.6 ± 4.8% and 71.6 ± 6.3%). Meranzin hydrate (30, 100 μmol/L) directly increased the amplitude of rat ileum compared with the control (P < 0.01). The pharmacokinetics profiles of meranzin hydrate and ferulic acid in patient plasma was fitted with a two-compartment model detected by a simple, rapid and accurate UPLC method. Time to reach peak concentration of meranzin hydrate (0.371 mg/L) and ferulic acid (0.199 mg/L) was 23.57 min and 27.50 min, respectively. The elimination half-life and area under the concentration-time curve from t = 0 to the last time of meranzin hydrate and ferulic acid were 139.53 min and 31.445 μg min/mL and 131.27 min and 14.835 μg min/mL, respectively. The absorption constant and volume of distribution of meranzin hydrate and ferulic acid were 0.185 ± 0.065 min⁻¹ and 3782.89 ± 2686.72 L/kg and 0.524 ± 0.157 min⁻¹ and 11713 ± 7618.68 L/kg, respectively. The experimental results of the pharmacokinetic parameters of meranzin hydrate and ferulic acid indicate that they were absorbed and distributed rapidly.

Conclusions

The pharmacodynamics and pharmacokinetics of prokinetic Chaihu-Shugan-San and its compounds are useful for monitoring Chaihu-Shugan-San formulas in clinical practice and for understanding therapeutic mechanisms.     

Pharmacokinetic study of salvianolic acid A in beagle dog after oral administration by a liquid chromatography–mass spectrometry method: A study on bioavailability and dose proportionality

Ethnopharmacological relevance

Salvianolic acid A (SAA) is one of the main water-soluble components isolated from Salvia miltiorrhiza Bunge. Pharmacological researches revealed that it had various curative activities after oral and intravenous administration, including beneficial effects on diabetes and its complications, cardioprotective effect, anti-platelet aggregation, and so on. However, there is no report regarding the pharmacokinetics of SAA in beagle dogs after oral administration up to now.

Aim of the study

To study the pharmacokinetics of different doses of SAA in beagle dogs and figure out the absolute bioavailability and dose proportionality of SAA after oral administration.

Materials and methods

Male and female beagle dogs were orally administered SAA 5, 10 and 20 mg/kg randomly. The plasma drug concentration was detected by a rapid, sensitive and reproducible liquid chromatography–mass spectrometry (LC–MS) method. The pharmacokinetic parameters were calculated from plasma concentration–time data using the DAS pharmacokinetic software Data Analysis System Version 3.0 program.

Results

After single-dose oral administration of SAA, the mean peak plasma concentration (C_max) values for groups treated with 5, 10 and 20 mg/kg doses ranged from 14.38 to 38.18 µg/L, and the mean area under the concentration–time curve (AUC_(0–t)) values ranged from 38.77 to 130.33 (µg/L⋅ h). SAA showed lack of dose proportionality over the dose range 5–20 mg/kg, based on the power model. However, the increase in systemic exposure with dose appeared linear. The absolute bioavailability was calculated to range from 1.47% to 1.84%.

Conclusion

The pharmacokinetic properties of SAA in beagle dogs after oral administration were characterized as rapid oral absorption, quick clearance, and poor absolute bioavailability. Systemic exposure exhibited lack of dose proportionality over the dose range 5–20 mg/kg. Furthermore, a readily preparative LC–MS method was demonstrated in this study for the research of traditional Chinese medicine.     

A UPLC–MS/MS method for in vivo and in vitro pharmacokinetic studies of psoralenoside,isopsoralenoside, psoralen and isopsoralen from Psoralea corylifolia extract

Ethnopharmacological relevance

The dried fruit of Psoralea corylifolia L. has been used to prevent and treat vitiligo, osteoporosis, arthralgia and asthma in Traditional Chinese Medicine for some 1600 years. Psoralen (P), isopsoralen (IP), psoralenoside (PO) and isopsoralenoside (IPO) are the major coumarins and coumarin-related benzofuran glycosides in Psoraleae Fructus, which have been reported to show estrogen-like activity, osteoblastic proliferation accelerating activity, antitumor effects and antibacterial activity. The first aim of this study is to develop a rapid, sensitive and selective ultra performance liquid chromatography tandem mass spectrometry (UPLC–MS/MS) approach for simultaneous determination of PO, IPO, P and IP in rat plasma and samples collected from in vitro incubation experiments. The second aim is to investigate the pharmacokinetic properties of PO, IPO, P and IP after oral administration of Psoralea corylifolia extract (PCE) to rats. The third aim is to confirm the biotransformation of PO to P or IPO to IP under gastrointestinal conditions.

Materials and methods

A UPLC–MS/MS method with a C18 column and a mobile phase of methanol-0.1% aqueous formic acid was validated according to the criteria in FDA guidelines about bioanalytical method, which was developed to investigate the pharmacokinetic behavior of PO, IPO, P and IP from PCE and the metabolic pathways of PO to P or IPO to IP.

Results

The criteria for establishment of a new UPLC–MS/MS method including selectivity, linearity, accuracy, precision, extraction recovery, matrix effect and stability were validated. This method was successfully applied to the quantitative determination of PO, IPO, P and IP in biological samples collected from both in vitro incubations and in vivo rat experiments. After oral administration of PCE to rat, pharmacokinetic parameters of these four compounds indicated that in vivo biotransformation may occur between PO and P or IPO and IP. Purified benzofuran glycosides fraction (PBGF), containing only PO and IPO, was orally administered to rats to further confirm the biotransformation of PO to P or IPO to IP under gastrointestinal conditions. An in vitro incubation study elucidated that PO and IPO were metabolized to P and IP by intestinal microflora through de-glucosylation.

Conclusions

This paper developed a rapid, sensitive and selective UPLC–MS/MS method for simultaneous determination of PO, IPO, P and IP from PCE in biological samples, and investigated on their comprehensive in vivo and in vitro pharmacokinetic studies. These obtained results showed that the metabolism by intestinal bacteria plays an important role in pharmacological effects of orally administered PCE.