Mechanistic understanding of the different effects of Wuzhi Tablet (Schisandra sphenanthera extract) on the absorption and first-pass intestinal and hepatic metabolism of Tacrolimus (FK506). Int J Pharm

Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University City, Guangzhou 510006, China.
International Journal of Pharmaceutics (Impact Factor: 3.65). 04/2010; 389(1-2):114-21. DOI: 10.1016/j.ijpharm.2010.01.025
Source: PubMed


We recently reported that the blood concentrations of Tacrolimus (FK506) in rats were markedly increased following the intake of a Chinese herbal preparation, Wuzhi Tablet (WZ, Schisandra sphenanthera extract). In order to identify the underlying mechanisms of the increase in FK506 level, we investigated the effects of WZ on the absorption and first-pass intestinal and hepatic metabolism of FK506 in vitro and in vivo. When co-administered with WZ, the AUC(0-infinity) value after oral FK506 dosing was increased by 2.1 fold, the oral bioavailability (F(oral)) was increased from 5.4% to 13.2% (p=0.0002), and the (F(abs) x F(G)) was 111.4% (p<0.01), much greater than that when FK506 was given alone. However, the F(H) was only 21.2% greater than that when FK506 was given alone, which indicates that the reduction of intestinal first-pass effect was the major cause of the increased FK506 oral bioavailability when co-administered with WZ. In the Caco-2 cell transport study, the transport ratio of FK506 with WZ extract was significantly lower than that of FK506 alone, which suggested WZ extract inhibited P-gp-mediated efflux of FK506. Furthermore, 100 microM of WZ extract almost completely inhibited FK506 metabolism in rat and human liver microsomes, indicating WZ extract potently inhibited the CYP3A-mediated metabolism of FK506. In conclusion, WZ inhibited P-gp-mediated efflux and CYP3A-mediated metabolism of FK506, and the reduction of intestinal first-pass effect by WZ was the major cause of the increased FK506 oral bioavailability.

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Available from: Xiao Chen, Feb 28, 2015
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    • "The WZ extract used in the in vitro experiment was prepared according to our previously published study (Qin et al. 2010). Briefly, 30 times (V: W) of ethanol (ml) was added into pulverized powder of WZ tablet (g) and vortexed for 1 min. "
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    ABSTRACT: Cisplatin is a potent anti-cancer agent for various types of tumors. However, the clinical use of cisplatin is often limited by its nephrotoxicity. This study reports that WZ tablet (WZ, a preparation of an ethanol extract of Schisandra sphenanthera) mitigates cisplatin-induced toxicity in renal epithelial HK-2 cells and in mice. Pretreatment of HK-2 cells with WZ ameliorated cisplatin-induced cytotoxicity caused by oxidative stress, as was demonstrated by reductions in the levels of reactive oxygen species (ROS) and increased levels of glutathione (GSH). WZ facilitated the nuclear accumulation of the transcription factor NF-E2-related factor 2 (Nrf2) and the subsequent expression of its target genes such as quinine oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1) and glutamate cysteine ligase (GCL). Protective effects of WZ on cisplatin-induced nephrotoxicity were also observed in mice. WZ attenuated cisplatin-induced renal dysfunction, structural damage and oxidative stress. The nuclear accumulation of Nrf2 and its target genes were increased by WZ treatment. Taken together, these findings demonstrated WZ have a protective effect against cisplatin-induced nephrotoxicity by activation of the Nrf2 mediated defense response, which is of significant importance for therapeutic intervention in cisplatin induced renal injury. Copyright © 2015 Elsevier GmbH. All rights reserved.
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    • "In addition, the intestinal CYP3A and P-gp contribute to a great extent to the first-pass metabolism of many CYP3A and P-gp substrates (Andersen et al., 2002; Paine et al., 2005; Hao et al., 2007; Kato, 2008). The reduction of intestinal first-pass effect of tacrolimus by WZC through CYP3A and P-gp is extensive and contributes greatly to the increase in tacrolimus bioavailability (Venkataramanan et al., 1990; Qin et al., 2010b).Therefore, it is useful to dissect the influence of WZC on regulating intestinal and hepatic CYP3A and P-gp for a better understanding of its differential effect in regulating pharmacokinetic profiles of tacrolimus. The related study will be addressed in our future study. "
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    ABSTRACT: Wuzhi capsule (WZC) is a preparation of an ethanol herbal extract of Schisandra sphenanthera(Nan-Wuweizi), with its main active ingredients including schisandrin, schisandrol B, schisantherin A, schisanhenol and deoxyshisandrin. WZC and tacrolimus are often co-administered for the treatment of drug-induced hepatitis in organ transplant recipients in China. Recently, it was reported that WZC could significantly increase the blood concentration of tacrolimus. The purpose of this study was to investigate whether and how WZC affects the pharmacokinetics of tacrolimus in rats. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to determine the plasma concentration of tacrolimus. The results showed that WZC increased the mean plasma concentration of tacrolimus. Compared with administration of tacrolimus alone (Cmax, 18.87±10.29 ng/mL; AUC0&→t, 40.98±37.07), a single intragastric administered dose of WZC increased, the pharmacokinetic parameters of tacrolimus (Cmax, 59.42±30.32 ng/mL; AUC0→t, 239.71±28.86) by five folds in rat plasma. After pretreatment with WZC for 12 days, there were still significant increases in AUC0→t (from 40.98±37.07 to 89.21±26.39 h ng/mL; p < 0.05) and Cmax (from 18.87±10.29 to 43.16±10.61 ng/mL; p < 0.05) of tacrolimus compared with oral of tacrolimus alone, suggesting that WZC increased the exposure of tacrolimus by one or more mechanisms. The increase in tacolimus Cmax by WZC was dose dependent. The effect of WZC on Tacrolimus AUC0→t also increased with dose with a maximal effect observed at 450 mg/kg (825.34 ng h/mL). No further increases in tacolimus AUC0→t were observed at WZC dose above 450 mg/kg. It is suggested that due to the effect of WZC on the pharmacokinetics of tacrolimus, the herb-drug interaction between WZC and tacrolimus should be taken into considered in clinical practice.
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    • "Lipid-based formulations specially SMEDDS improve as well as normalize drug absorption, which is particularly beneficial for low therapeutic index drug like tacrolimus. These formulations enhance absorption by a number of mechanisms like improving drug solubility and maintaining drug in solution state throughout GI tract, inhibition of P-glycoprotein-mediated drug efflux and pre-absorptive metabolism by gut membrane-bound cytochrome enzymes,[89] the promotion of lymphatic transport, which delivers drug directly to the systemic circulation. Although avoiding hepatic first-pass metabolism,[10] and also by increasing GI membrane permeability.[11] "
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    ABSTRACT: Tacrolimus has poor solubility in water ranging from 4 to 12 μg/mL. The oral bio availabilities of tacrolimus is poor and exhibits high intra and inter-subject variability (4-89%, average 25%) in the liver and the kidney transplant recipients and in patients with renal impairment. The present study deals with the development and characterization of self-micro-emulsifying drug delivery system to improve the oral bioavailability of poorly soluble drug tacrolimus. Solubility of the tacrolimus was estimated in various oils, surfactants, and co-surfactants. Various in vitro tests such as percentage transmittance, emulsification time, cloud point, precipitation, and thermodynamic stabilities were used to find out optimized formulations. Optimized liquid self micro-emulsifying (SMEDDS) were characterized by particle size analysis and converted in solid by using the Florite RE as an adsorbent, which is further characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and particle size analysis. The optimized liquid SMEDDS formulation contained 10% Lauroglycol FCC as an oil, 60% Cremophor RH, and 30% PEG (polyethylene glycol) 400 as a surfactant and co-surfactant respectively. The optimized liquid and solid SMEDDS showed higher drug release than the marketed capsule and pure API (active pharmaceutical ingredient) powder. For optimized liquid SMEDDS and solid SMEDDS, the globule sizes were found 113 nm and 209 nm respectively. The solid state characterization of solid-SMEDDS by SEM, DSC, FTIR, and XRD revealed the absence of crystalline tacrolimus in the solid-SMEDDS. Shelf-lives for liquid SMEDDS and solid SMEDDS were found to be 1.84 and 2.25 year respectively. The results indicate that liquid SMEDDS and solid SMEDDS of tacrolimus, owing to nano-sized, have potential to enhance the absorption of the drug.
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