Zipeng Gong

Pharmacokinetic comparison of berberine in rat plasma after oral administration of berberine hydrochloride in normal and post inflammation irritable bowel syndrome rats.

In the present study, post inflammation irritable bowel syndrome (PI-IBS) rats were firstly established by intracolonic instillation of acetic acid with restraint stress. Then the pharmacokinetics of berberine in the rat plasma were compared after oral administration of berberine hydrochloride (25 mg/kg) to normal rats and PI-IBS rats. Quantification of berberine in the rat plasma was achieved by using a sensitive and rapid UPLC-MS/MS method. Plasma samples were collected at 15 different points in time and the pharmacokinetic parameters were analyzed by WinNonlin software. Compared with the normal group, area under the plasma concentration vs. time curve from zero to last sampling time (AUC0–t) and total body clearance (CL/F) in the model group significantly increased or decreased, (2039.49 ± 492.24 vs. 2763.43 ± 203.14; 4999.34 ± 1198.79 vs. 3270.57 ± 58.32) respectively. The results indicated that the pharmacokinetic process of berberine could be altered in PI-IBS pathological conditions.

Pharmacokinetics of Two Alkaloids after Oral Administration of Rhizoma Coptidis Extract in Normal Rats and Irritable Bowel Syndrome Rats

A comparative pharmacokinetic study of berberine and palmatine after oral administration of Rhizoma Coptidis extract (96 mg/kg, containing berberine 22 mg/kg and palmatine 5 mg/kg based on body weight) was performed in normal and postinflammation irritable bowel syndrome (PI-IBS) rats, induced by intracolonic instillation of acetic acid and restraint stress. Quantification of berberine and palmatine in rat plasma was achieved by using a sensitive and rapid UPLC-MS/MS method. Plasma samples were collected at 13 different time points and the pharmacokinetic parameters were analyzed by WinNonlin software. The significant differences in the pharmacokinetic behaviors, such as C max⁡, AUC(0–t), V d/F, and CL/F, of berberine and palmatine were found between normal and PI-IBS model rats. The results indicated that PI-IBS pathological conditions in rats could alter the pharmacokinetic behavior of drug. Preclinical pharmacokinetic studies are usually carried out on healthy animals. However, we should pay more attention to the fact that the change of pharmacokinetic behavior plays an important role on efficacy. It is essential to investigate the pharmacokinetics of the drug in disease status.

Studies on Efficacy Mechanism of Chinese Herbal Combination Based on Drug metabolizing Enzyme

Mixed Formula is the main form and method of Traditional Chinese Medicine (TCM) treatment. It can produce different therapeutic effects by changing the combination of TCM Formula. Wuji Wan is a formula of TCM and was composed of Rhizoma Coptidis (Huanglian in Chinese, HL), Fructus Evodiae Rutaecarpae (Wuzhuyu, WZY) and Radix Paeoniae Alba (Baishao, BS). Wuji Wan is mainly used for the treatment of intestinal diseases. This paper took Wuji Wan as example study on efficacy Mechanism of TCM Combination Based on drug metabolizing Enzyme. Inhibition of cytochrome P450 (CYP) is regarded as the most clinically important pharmacokinetic causes among the various possible factors for drug-drug or herb-herb/herb-drug interactions. In this study, the in vitro inhibitory effects of Wuji Wan with different combination within HL, WZY and BS on six major rat CYPs (CYP1A2, CYP2A6, CYP2C19, CYP2D6, CYP2E1 and CYP3A1/3A2) activities were examined by using HPLC and LC-MS. Wuji Wan with different combination were designed as 9 Formulae according to orthogonal table L9 (34); meanwhile the inhibitory effects of the single herb HL, WZY and BS also were done and compared with 9 Wuji Wan Formulae with different combination. Results demonstrated that BS showed negligible inhibitory effects on the six major CYP isoenzymes in rat liver microsomes, but HL showed strong inhibitory effects on 6 CYPs with almost all of the IC50 values below 200 μg (crude drug)•mL-1, and WZY showed a little bit inhibitory effects on 6 CYPs with the IC50 values between 870-2000 μg (crude drug)•mL-1; moreover, 9 Wuji Wan Formulae showed different inhibitory characteristic following with the dose levels of HL, WZY and BS in L9(34) design. In conclusion, this study demonstrates that Wuji Wan is likely to cause significant herb-drug interactions in humans when co-administered with substrates of the six CYPs (CYP1A2, CYP2A6, CYP2C19, CYP2D6, CYP2E1 and CYP3A)and also the different inhibitory effects on cytochrome P450 of Wuji Wan within different combination could be one of the reasons for explaining the different combination of TCM Formula producing different therapeutic effects, because the chemical composition of TCM in vivo (prototype or metabolites) is the Material basis of TCM effects.

Wuji Wan Formula Ameliorates Diarrhea and Disordered Colonic Motility in Post-inflammation Irritable Bowel Syndrome Rats by Modulating the Gut Microbiota

Emerging evidence suggests that gut microbiota contribute to the treatment of post-inflammatory irritable bowel syndrome (PI-IBS). Our previous studies have demonstrated that a Chinese formula, Wuji Wan, has the ability to mitigate abdominal pain and diarrhea in PI-IBS rats. However, little is known about the underlying mechanism and whether the gut microbiota mediate the effect of Wuji Wan on PI-IBS. Thus, the aim of this study was to determine whether Wuji Wan mitigated PI-IBS by modifying the gut microbiota. PI-IBS was induced in Sprague-Dawley rats by enema using 4% acetic acid and restraint stress. Rats were fed water, Wuji Wan extract (630 mg/kg) or pinaverium bromide (13.5 mg/kg). Our data showed that Wuji Wan effectively ameliorated abdominal pain, colonic motility abnormality and visceral hypersensitivity. Analysis of the fecal microbiota showed that Wuji Wan could reverse the reduction in richness of the gut microbiota and significantly increase the relative abundances of Akkermansia, Bacteroides, and Parasutterella; however, Lactobacillus and Prevotella were markedly decreased in the PI-IBS rats. Moreover, Wuji Wan promoted goblet cell proliferation in the colonic mucosa by increasing the release of mucin, up-regulating the distribution of tight junction proteins Occludin and ZO-1 and down-regulating the expression of MLCK in colonic epithelial cells. These findings suggest that Wuji Wan may remit IBS by modulating the gut microbiota and stabilizing the gut mucosal barrier, indicating that the use of a classical formula of Traditional Chinese Medicine (TCM) that exhibits a prebiotic effect may be a promising strategy for PI-IBS treatment.