Effect and safety of Tripterygium Hypoglaucum (Lévl.) hutch in treating proteinuria of kidney transplant recipients.

OBJECTIVE: To investigate the therapeutic and adverse effects of Tripterygium hypoglaucum (Lévl.) Hutch (THH) in treating proteinuria of renal transplant recipients. METHODS: Thirty patients with proteinuria greater than 1 g/24 h were enrolled to be treated with one tablet preparation of THH extract (360 mg, 3 times daily, equivalent to triptolide 30 µg/d) for 6 months. The proteinuria, serum creatinine, sex hormones, semen analysis and erectile function in male were determined at entry, 3 and 6 months. Incidence of adverse events was evaluated. RESULTS: THH treatment significantly improved proteinuria (from 2.52±1.87 g/d at baseline to 1.11±0.96 g/d at 3 months, and to 1.04±1.09 g/d at 6 months). No significant changes were observed in serum creatinine, liver enzymes or complete blood count. In female (15 cases), THH treatment induced a significant increase in follicle stimulating hormone and luteinizing hormone levels, and a significant decrease in estradiol and progesterone levels, and the main adverse effects were reversible menstrual irregularities (73.3% at 6 months). In male (15 cases), the sperm concentration and viability were markedly decreased by THH treatment, but the sex hormone levels and erectile function did not change significantly by treatment. CONCLUSIONS: THH is effective and safe for the treatment of proteinuria in renal transplant recipients. Its primary adverse effect is reversible toxicity to reproductive organs. Further controlled clinical trials are warranted to determine the true clinical benefit of THH.

In vivo to in vitro effects of six bioactive lignans of Wuzhi tablet (Schisandra sphenanthera extract) on the CYP3A/P-glycoprotein-mediated absorption and metabolism of tacrolimus.

We recently reported that Wuzhi tablet (WZ; Schisandra sphenanthera extract) can inhibit P-glycoprotein (P-gp)-mediated efflux and CYP3A-mediated metabolism of tacrolimus (FK506) and thus increase the blood concentrations of FK506. Major active lignans of WZ include schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, and schisantherin A. Whether and how these six lignans affect the pharmacokinetics of FK506 remains unclear. Therefore, this study aimed to investigate the effects of these lignans on the first-pass absorption and metabolism of FK506 and the involved mechanisms in vitro and in vivo. The results showed that whole-blood concentrations of FK506 were increased to different degrees following coadministration of the six lignans, respectively. Schisandrol B showed the strongest effect on the increase of the area under the concentration-time curve, the oral bioavailability, the gut processes affecting availability, and the hepatic availability of FK506. The reduction of intestinal first-pass effect contributed most to the increase in oral bioavailability of FK506 when coadministered with schisandrol B. In vitro transport experiment showed that schisandrin A, schisandrin B, and schisandrol B inhibited P-gp-mediated efflux of FK506. In vitro metabolism study showed that the inhibitory effect of these six lignans on FK506 metabolism was dose-dependent. In conclusion, the exposure of FK506 in rats was increased when coadministered with these lignans, and schisandrol B showed the strongest effect. Lignans of WZ inhibited P-gp-mediated efflux and CYP3A-mediated metabolism of FK506, and the reduction of intestinal first-pass affected by the lignans was the major cause of the increased FK506 oral bioavailability.

Effects of ligustrazine on ureteral obstruction-induced renal tubulointerstitial fibrosis.

Ligustrazine (LIG) is a purified and chemically identified component of the Chinese herb Ligusticum wallichii Franchat. It is a potent blocker of vasoconstriction and has strong scavenger of oxygen free radicals. We investigated the effect of LIG on renal tubulointerstitial fibrosis using a rat model of unilateral ureteral obstruction. Ligustrazine treatment significantly reduced the scores of interstitial collagen deposition, amounts of hydroxyproline, the density of myofibroblasts and macrophages, and amounts of transforming growth factor-ß1 (TGF-ß1) and connective tissue growth factor (CTGF) compared with their level in a saline-treated control group. Using quantitative polymerase chain reaction we found that LIG treatment significantly reduced the mRNA expression of TGF-ß1, CTGF, monocyte chemoattractant protein-1 and osteopontin. Moreover, the mRNA expression of hepatocyte growth factor and bone morphogenetic protein-7 were significantly increased by LIG. In vitro, LIG inhibited the TGF-ß1-induced loss of cytokeratin-18 expression and de novo increase of the expression of α-smooth muscle actin of HK-2 cells in a dose-dependent manner, which suggested that LIG could restrain the process of epithelial-myofibroblast transition of tubular epithelial cells. This study indicates that LIG can attenuate renal tubulointerstitial fibrosis. It might be useful as a potential candidate in the treatment of chronic renal diseases.

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).

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.

Study of the effect of Wuzhi tablet (Schisandra sphenanthera extract) on tacrolimus tissue distribution in rat by liquid chromatography tandem mass spectrometry method.

A liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated for determining tacrolimus (FK506) in rat tissues to study the effect of Schisandra sphenanthera extract on FK506 tissue distribution. After a liquid-liquid extraction with ethyl acetate, FK506 and ascomycin (IS) were subjected to LC-MS/MS analysis using positive electrospray ionization under multiple reactions monitoring mode. Chromatographic separation of FK506 and ascomycin was achieved on a Hypersil BDS C(18) column with a mobile phase consisting of methanol-water (containing 2 mM ammonium acetate, 95 : 5, v/v). The intra- and inter-batch precision of the method were less than 8.8 and 9.8%, respectively. The intra- and inter-batch accuracies ranged from 97.5 to 104.0%. The lowest limit of quantification for FK506 was 0.5 ng/mL. The method was applied to a FK506 tissue distribution study with or without a dose of Wuzhi (WZ) tablet. Most of the FK506 tissue concentrations were slightly increased after a concomitant WZ tablet dose, but the whole blood concentration of FK506 was dramatically increased 3-fold after a concomitant WZ tablet dose. These results indicated that the LC-MS/MS method was rapid and sensitive enough to quantify FK506 in different rat tissues, and strict drug monitoring is recommended when co-administering WZ tablet in clinical use.