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Effect of Tacrolimus on the pharmacokinetics of bioactive lignans of Wuzhi tablet (Schisandra sphenanthera extract) and the potential roles of CYP3A and P-gp.

ABSTRACT

We recently reported that Wuzhi tablet (WZ), a preparation of the ethanol extract of Wuweizi (Schisandra sphenanthera), had significant effects on blood concentrations of Tacrolimus (FK506) in renal transplant recipients and rats. The active lignans in WZ are schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, schisantherin A, and schisantherin B. Until now, whether the pharmacokinetics of these lignans in WZ would be affected by FK506 remained unknown. Therefore, this study aimed to investigate whether and how FK506 affected pharmacokinetics of lignans in WZ in rats and the potential roles of CYP3A and P-gp. After a single oral co-administration of FK506 and WZ, the blood concentration of lignans in WZ was decreased by FK506; furthermore, the AUC of schisantherin A, schisandrin A, schisandrol A and schisandrol B was only 64.5%, 47.2%, 55.1% and 57.4% of that of WZ alone group, respectively. Transport study in Caco-2 cells showed that these lignans were not substrates of P-gp, suggesting decreased blood concentration of lignans by FK506 was not via P-gp pathway. Metabolism study in the human recombinant CYP 3A showed that these lignans had higher affinity to CYP3A than that of FK506, and thus had a stronger CYP3A-mediated metabolism. It was concluded that the blood concentrations of these lignans were decreased and their CYP3A-mediated metabolisms were increased in the presence of FK506 since these lignans had higher affinity to CYP3A.

Keywords:

Tacrolimus

Schisandra sphenanthera extract

Wuzhi tablet

Lignans

Pharmacokinetics

Herb-drug interaction

Introduction

Schisandrae Sphenantherae Fructus (Wuweizi) is the dried ripe fruit of Schisandra Sphenanthera Rehd. et Wils. It is historically listed among China's most important herbs to improve the function of the liver, kidney and heart and it is now indexed in Chinese Pharmacopoeia (Pharmacopoeia of the People's Republic of China, 2010). Today it is popular worldwide both as a readily available tonic and dietary supplement. This natural product and its individual active components from the extract mixture have been extensively studied and are known to exhibit multiple pharmacological activities in particular hepatoprotective effects. The whole extract and the active lignans in the extract have been well proven to possess hepatoprotective effect against the hepatic dysfunction induced by various chemical hepatotoxins such as carbon tetrachloride (C[Cl.sub.4]) (Xie et al., 2010; Zhu et al., 2000).

Wuzhi tablet (WZ) is one of the preparations of ethanolic extract of Wuweizi (Schisandra sphenanthera), which contains 7.5 mg of schisantherin A per tablet. Its major active lignans include schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, and schisantherin A (Fig. 1) (Huyke et al., 2007). WZ is a prescribed drug (registration number in China: Z20025766) rather than a herbal supplement, and is used in clinical practice to protect liver function in chronic hepatitis and liver dysfunction patients (Loo et al., 2007).

Tacrolimus (FK506, Fig. 1) is a well-known potent immunosuppressant indicated in prevention and/or treatment of graft rejection in solid organ transplantation patients (Mentzer et al., 1998; Staatz and Tett, 2004; Bowman and Brennan, 2008). Despite its effective immunosupressant activity, long-term treatment with FK506 may cause sever liver damage (Sacher et al., 2012; Fisher et al., 1995; Emre et al., 2000; Taniai et al., 2008). In China, WZ is often prescribed with FK506 when drug-induced hepatitis or liver dysfunction occurs in transplant patients.

Many reports including our previous studies have indicated that blood concentrations of FK506 were increased in the presence of Schisandra sphenanthera extract in transplant recipients and in rats (Jiang et al., 2010; Jin et al., 2011; Qin et al., 2010a,b, 2013; Wei et al., 2013; Xin et al., 2011, 2007). Our previous studies in rats indicated that long-term and short-term treatment with WZ significantly increased the FK506 whole blood concentration (Qin et al., 2010a,b, 2013). Additionally, our study indicated that WZ inhibits P-gp-mediated efflux and CYP3A-mediated metabolism of FK506, and the reduction of the intestinal first-pass effect by WZ was the major cause of the increased FK506 oral bioavailability (Qin et al., 2010b). However, whether and how the pharmacokinetics of lignans in WZ was affected by FK506 remain unknown. To elucidate the herb-drug interaction between WZ and FK506, it is very important to know the effect of FK506 on the pharmacokinetic behavior of the bioactive lignans in WZ, such as schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, and schisantherin A. Therefore, the current study was aimed to investigate the effect of FK506 on the pharmacokinetic behavior of bioactive lignans of WZ in rats and the potential roles of CYP3A and P-gp in vitro.

Materials and methods

Chemicals and reagents

The crude dried fruits of Schisandra Sphenanthera Rehd. et Wils meets the standard of the Pharmacopoeia of the People's Republic of China. The extract of Schisandra sphenanthera Fructus (batch No.: 110711) was manufactured and supplied by Fang Lue Pharmaceutical Company (Guangxi, China) under GMP guidelines. This 70% ethanol extract is formulated with starch, carboxymethyl starch sodium and magnesium stearate into tablets. The final product (WZ tablet) meets the China SFDA standard (YBZ14932006) and has been quantified to 7.5 mg schisantherin A per tablet by HPLC analysis. Pure compounds such as schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, and schisantherin A (Fig. 1) were all produced by Shanghai Winherb Medical Science and Technology Development Co., Ltd. (Shanghai, China, http://www.winherb.cn/). FK506 with a purity of 98% as determined by F1PLC with ultraviolet (UV) detection was synthesized and provided by Toronto Research Chemicals Inc. (Toronto, Canada). Ascomycin (FK520, as the internal standard, IS, see Fig. 1) with a purity of 95% as determined by F1PLC with UV detection was synthesized and provided by BIOMOL Research Laboratories Inc. (Plymouth Meeting, PA). Prograf[R] capsules (1 mg of FK506 per capsule) were produced by Astellas Ireland Co., Ltd. (Ireland). Methanol and acetonitrile of FIPLC grade were purchased from Tedia Inc. (Beijing, China). All other reagents were of analytical grade or HPLC grade where appropriate. Ultra-pure water was obtained from a Milli Q-plus system (Billerica, MA).

Fingerprint analysis of Wuzhi tablet

Wuzhi tablet (WZ) was prepared for fingerprint analysis. Briefly, WZ were crushed to powder and then extracted with ethanol (1.0g in 10ml ethanol) in an ultrasonic bath for 60min at room temperature. The extracted solution was centrifuged at 1500 x g for 5 min. The supernatant was collected and filtered through a 0.22 [micro]m membrane filter prior to HPLC analysis. An aliquot of 5 [micro]l solution was injected for HPLC analysis. The standard solutions of six reference lignans were prepared by weighing the compounds accurately and dissolving them with ethanol.

Chromatographic analysis was performed on a SHIMADZU LC20AD high performance liquid chromatography (HPLC) system equipped with a photo diode array (PDA) detector (190-800 nm), a binary solvent delivery system, a column temperature controller and an autosampler. The chromatographic data were processed with SHIMADZU LCsolution Work Station software. Chromatographic separation was performed on a Hypersil BDS C18 column (150 mm x 4.6 mm i.d., 5 [micro]m) at 35[degrees]C. The mobile phase consisted of eluents A (water) and B (acetonitrile). The elution program was optimized and conducted as follows: a linear gradient of 40-48% B (0-8 min), an isocratic elution of 48% B (8-25 min), a linear gradient of 48-70% B (25-40 min), a linear gradient of 95-100% B (41-50 min), a linear gradient of 100-40% B (50-51 min) and 40% B (51-60 min). The peaks were recorded using PDA absorbance at 254 nm and the solvent flow rate was kept at 1.0 ml/min. The wavelength of detector was set at 254 nm, and the online ultraviolet absorption spectra were recorded in the 190-800 nm range.

Animals

Male Sprague-Dawley rats weighing between 220g and 260 g were supplied by the Laboratory Animal Service Center at Sun Yatsen University (Guangzhou, China). The animals were kept in a room at 22-24[degrees]C with a light/dark cycle of 12/12 h and 55-60% relative humidity. They had free access to standard rodent food and water. The rats were fasted for 12 h before the pharmacokinetic interaction study. All procedures were in accordance with the Regulations of Experimental Animal Administration issued by the Ministry of Science and Technology of the People's Republic of China (http://www.most.gov.cn). The animal study protocols were approved by the Institutional Animal Care and Use Committee (IACUC) at Sun Yat-sen University, Guangzhou, China.

Pharmacokinetic study in rats

On the day before the experiment, a light surgery on the right jugular vein for the rat was performed as described in our previously published paper (Jin et al., 2011; Qin et al., 2010a,b, 2013). Afterwards, the rats were placed individually in cage, allowed to recover and fasted for 12 h before the pharmacokinetic study.

The rats were randomly divided into two groups. A single dose of FK506 (1.89mg/kg) or water was given by gavage 1 min before the oral administration of WZ (0.25 g/kg). Rats were then deprived of water for 2 h and fasted for 4 h. Approximately 0.25 ml of blood samples via the right jugular vein were collected in a pre-heparinized tube at pre-dosing (Oh) and at 5,15,30,45 min, 1,1.5, 2, 3, 4, 6, 8, 12, and 24 h post-dosing. After blood sampling, the cannula was flushed with an equal volume of heparinized saline solution (50 U/ml) to prevent coagulation and to replace the blood loss. 200 [micro]l of the blood sample was immediately collected and stored at -20[degrees]C until analysis.

Transport of lignans in WZ in Caco-2 cells

Caco-2 cells were cultured and used as previously described in our paper (Qin et al., 2010b; Zhang et al., 2006). The transport of the active lignans (2 [micro]M)) of WZ across Caco-2 monolayer was investigated by the methods described previously (Qin et al., 2010b; Zhang et al., 2006; Bi et al., 2008) with small modifications.

Metabolism of lignans in WZ in human recombinant CYP3A4 and CYP3A5 system

The metabolism of lignans in WZ was investigated by the methods described previously (Qin et al., 2010b) with some modifications. Briefly, the human recombinant CYP3A4 (rCYP3A4) and CYP3A5 (rCYP3A5) (final concentration: 12.5 pmol/ml) were incubated for 5 min at 37[degrees]C in the presence of an NADPH-gs and 0.1 mM EDTA with or without ketocanazole (10|xM). The reaction was started by addition of 20 [micro]l of lignans solution (final concentration: 0.1 [micro]M) to the system. The mixture was incubated for 5 min at 37[degrees]C; then, the reaction was stopped by 400 [micro]L ice-cold acetonitrile. Lignans were determined by LC-MS/MS method described below.

Quantification of lignans in WZ by LC-MS/MS method

Samples were prepared using the procedure described in our previous report with slight modifications (Qin et al., 2010a,b, 2013; Li et al., 2008).

The chromatographic separation was achieved by using a [C.sub.18] column (Hypersil BDS [C.sub.18], 3 [micro]m particle size, i.d. 50 mm x 2.1 mm, Elite HPLC Inc., Dalian, China) at room temperature. The mobile phase consisted of methanol-water (95:5, v/v, containing 2mM ammonium acetate), pumped at a flow rate of 200 [micro]l/min. The total running time was 2 min for each sample.

The MS/MS detection was conducted by monitoring the fragmentation of m/z 417.1 [right arrow] 316.1 for Schisandrin A, m/z 401.3 [right arrow] 300.4 for Schisandrin B, m/z 385.3 [right arrow] 285.3 for Schisandrin C, m/z 433.1 [right arrow] 384.1 for Schisandrol A, m/z 417.4 [right arrow] 368.3 for Schisandrol B, m/z 599.0 [right arrow] 415.1 for Schisantherin A, and m/z 809.5 [right arrow] 756.4 for FK520. The linear calibration curves were over the concentrations of 0.5-200 ng/ml for Schisandrin A, Schisandrin B, Schisandrol A, and Schisandrol B, 10-1000 ng/ml for Schisantherin A; and the lower limit of quantification (LLOQ) of the method was 0.5 ng/ml for lignans (except of Schisantherin A, which the LLOQ was 10 ng/ml). The linearity of the calibration curves was good with correlation coefficient [r.sup.2] > 0.98. The intra-and interbatch precisions (RSD %) were less than 15% for all quality control samples. The extraction recovery from the biological matrices were 44.7-53.9% for Schisandrin A, 42.3-48.6% for Schisandrin B, 37.2-40.5% for Schisandrin C, 52.0-60.1% for Schisandrol A, 55.7-60.0% for Schisandrol B and 50.2-52.8% for Schisantherin A. Lignans in WZ were stable under routine laboratory conditions.

Data analysis

Pharmacokinetic analysis was performed using a non-compartmental analysis by the Pharmacokinetics and Bioavailability Program Package (Version 2.1, Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-set University, Guangzhou, China) (Qin et al., 2010b, 2013; Bi et al., 2008). Statistical significances were evaluated using Student's t-tests. P value <0.05 was considered statistically significant.

Results and discussion

The HPLC fingerprint of WZ extract is illustrated in Fig. 2. Peaks in WZ fingerprint profile showed good peak shape and good resolution with their respective adjacent peaks, together with the six targeted lignans. The resolution of the two strongest peaks in HPLC profiles was more than 1.5, which met the requirement of herbal medicine fingerprint. The identity of chromatographic peaks in the WZ HPLC profiles was confirmed by comparing the retention time and the UV spectra with the reference compounds. This HPLC fingerprint of WZ extract was approximately consistent with a reported chromatogram for extract of Schisandra sphenanthera (Wei et al., 2010), which could be utilized as a quality evaluation method for WZ tablet. The relative amounts of lignans in WZ extract were compared and the results showed that Schisantherin A and Schisandrin A were the two highest bioactive lignans in WZ, and other lignans were much lower than the above contents, which was consistent with our previous published data (Qin et al., 2013). On the other hand, the representative chromatographic profiles of blank whole blood, a blood sample spiked with lignans and IS (FK520) and a blood sample from a rat after a single oral coadministration of WZ (0.25 g/kg) and FK506 (1.89mg/kg) as well as the extracted sample of WZ are shown in our resent published paper (Qin et al., 2013). No endogenous peak was observed at the retention times of lignans in WZ and IS.

The whole blood concentration-time curves of lignans after a single oral dose of WZ (0.25 g/kg) to rats with or without an oral dose of FK506 (1.89 mg/kg) are illustrated in Fig. 3 and the pharmacokinetic parameters of lignans are summarized in Table 1. At the oral dose of 0.25 g/kg of WZ, the blood concentrations of schisandrin B and schisandrin C were not detected under the current analytical conditions. After a single oral dose of WZ (0.25 g/kg) to rats, the AUC of schisantherin A, schisandrin A, schisandrol A and schisandrol B was 10812.8 [+ or -] 2796.8, 186.5 [+ or -] 95.0, 297.1 [+ or -] 123.1 and 209.7 [+ or -] 63.0 ng h/ml, respectively. While co-administered with FK506 (+FK506 group), the AUC of the above lignans was significantly decreased to 6980.6 [+ or -] 2935.6, 88.0 [+ or -] 26.4, 163.7 [+ or -] 72.7 and 120.4 [+ or -] 66.9 ng h/ml, respectively. It's obvious that the blood concentration of schisantherin A, schisandrin A, schisandrol A and schisandrol B was significantly decreased by FK506; and the AUC of schisantherin A, schisandrin A, schisandrol A and schisandrol B was only 64.5%, 47.2%, 55.1% and 57.4% of that of WZ alone group, respectively.

At the oral dose of WZ, the AUC of schisantherin A: schisandrin A: schisandrol A: schisandrol B was about 36:0.6:1:0.7 (in vivo). However, in WZ tablet extract, the content of schisantherin A: schisandrin A: schisandrol A: schisandrol B was about 210:150:1:10 (in vitro). In WZ extract, the content of schisantherin A:schisandrin A was only about 1.4:1, and the content of schisandrol B was 10 fold greater than that of schisandrol A. However, in vivo study showed that the AUC of schisantherin A was about 57 fold greater than that of schisandrin A, while the AUC of schisandrol B was only 0.7 fold of that of schisandrol A, which was much different from that of in vitro data. The reasons for these differences may be due to the different metabolic pathway or different bioavailability of lignans in vivo. For example, our further study showed that schisandrin A was metabolized to schisandrol A in mouse liver microsomes (data were not shown). These results indicated that in vitro data on contents of lignans in WZ could not represent that of in vivo. Therefore, it is not only necessary to characterize and measure the contents of lignans in WZ extract, but also necessary to measure the blood/plasma concentration of lignans in WZ in vivo.

Previously published work has shown that several constituents from Schisandra sphenanthera (wuweizi) could inhibit the activity of P-gp and CYP3A (Iwata et al., 2004; Qiangrong et al., 2005; Xu et al., 2005; Pan et al., 2006; Sun et al., 2007; Yoo et al., 2007). On the other hand, FK506 has also been shown to act as both substrate and/or inhibitor for CYP3A and P-gp (Hebert, 1997; Izuishi et al., 1997; Iwasaki, 2007). Therefore, FK506 would possibly influence the pharmacokinetic behavior of lignans in WZ by affecting CYP3A and/or P-gp.

To validate this hypothesis, Caco-2 cell model and recombinant human enzyme incubation system were employed to evaluate the transport and metabolism of lignans in WZ. Caco-2 transported study showed the transport ratios of schisandrin A, schisandrin B, schisandrol A, schisandrol B and schisantherin A were 0.76, 1.82, 1.30,0.96 and 0.98 (Table 2), respectively, suggesting these lignans were not substrates of P-gp and thus further suggesting decreased blood concentration of lignans by FK506 was not through P-gp pathway. On the other hand, the metabolism of schisandrin A, schisandrol A and schisandrol B was significantly inhibited in the presence of the typical CYP3A inhibitor ketoconazole in rCYP3A4 (Table 3) and rCYP3A5 (Table 4) incubation system, indicating that schisandrin A, schisandrol A and schisandrol B were the substrate of CYP3A4 and CYP3A5. The Km of schisandrin A, schisandrol A and schisandrol B to CYP3A4 and CYP3A5 was 0.064 and 0.050, 0.072 and 0.068, 2.0 x [10.sup.-6] and 0.05 [micro]M, respectively, which was much lower than that of FK506 (Km: 0.11 and 0.24 [micro]M) (Table 5), suggesting the affinity of schisandrin A, schisandrol A and schisandrol B to CYP3A4 and CYP3A5 was much higher than that of FK506. When Schisandrin A, schisandrol A, schisandrol B and FK506 were co-incubated in rCYP3A system, metabolism of these compounds would be occurred in a competitive manner. Schisandrin A, schisandrol A, schisandrol B with a higher affinity to CYP3A could result in a stronger metabolism by CYP3A. As a result, the blood concentration of these of lignans was decreased in vivo.

The Km of schisantherin A to CYP3A4 and CYP3A5 was not detectable. Iwata et al showed that the inhibitory effect of schisantherin A (gomisin C) on CYP3A was stronger than that of ketoconazole (Ki 0.070 [micro]M), a known potent CYP3A4 inhibitor (Iwata et al., 2004). The concentrations (0.1,0.25, 0.5,1 and 2 [micro]M) of schisantherin A used to calculate the Km to CYP3A in our current study was much higher than its own Ki value (0.049 [micro]M) (Iwata et al., 2004), which could result in a strong inhibition of metabolism of schisantherin A and thus its Km cannot be calculated using the current concentrations.

A number of studies as well as our present study have demonstrated that the Tacrolimus metabolism was significantly decreased when it is co-administered with other drugs (Plosker and Foster, 2000). But there is little report on the potential effect of FK506 on the metabolism of those concomitant drugs. It was reported that in dogs and in paediatric liver transplant patients FK506 may increase blood levels of cyclosporin, another CYP3A substrate (Wu et al., 1991; Furlan et al., 2000). Another study showed that FK506 noncompetitively inhibited CYP2E1, CYP2C11 and CYP3A4 (Izuishi et al., 1997). However, results from current study showed that the blood concentrations of lignans in WZ were decreased in the presence of FK506, which was different from previously reported study. Previous data from the human liver microsomes experiments suggested FK506 inhibited CYP3A in a competitive manner, with Ki values of 0.61 [micro]M (Amundsen et al., 2012). While the blood concentrations of FK506 in rat and in renal transplant patients were much lower than Ki value of FK506 (Qin et al., 2010a,b, 2013; Li et al., 2008). Thus, the inhibitory effect of FK506 on the CYP3A could be negligible, and it acts as a typical CYP3A substrate in the current case. Since those lignans have stronger affinity to CYP3A, the metabolism of those lignans was increased and the FK506 metabolism by CYP3A was decreased, which result in a decreased blood concentration of lignans in rats when WZ and FK506 was co-administered.

Conclusion

After a single oral co-administration of FK506 and WZ, the blood concentration of lignans in WZ was decreased by FK506; furthermore, the AUC of schisantherin A, schisandrin A, schisandrol A and schisandrol B was significantly decreased. Transport study in Caco2 cells indicated that decreased blood concentration of lignans by FK506 was not via P-gp pathway. Metabolism study in the human recombinant CYP 3A suggested that lignans in WZ and FK506 were both substrates of CYP3A, the affinity of lignans to CYP3A was much higher than that of FK506, and WZ successfully competed to a much more strong metabolism. Thus, higher affinity of lignans to CYP3A mainly contributed to a stronger metabolism of lignans and thus decreased blood concentration of lignans by FK506.

http://dx.doi.org/10.1016/j.phymed.2013.12.006

ARTICLE INFO

Article history:

Received 25 July 2013

Received in revised form 15 October 2013

Accepted 20 December 2013

Acknowledgement

We thank the Natural Science Foundation of China (Grant: 81001685), the Ministry of Education of China (Grant: 20100171120058), and the Science and Technology Foundation of Guangzhou (Grant: 2011J4300098) for financial support of this study.

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Xiao-ling Qin (a,b), Xiao Chen (c), *, Guo-ping Zhong (a), Xiao-mei Fan (a), Ying Wang (d), Xin-ping Xue (a), Ying Wang (a), Min Huang (a), Hui-chang Bi (a), *

(a) Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China

(b) Guangdong Food and Drug Vocational College, Guangzhou, China

(c) The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

(d) Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

* Corresponding author at: School of Pharmaceutical Sciences, Sun Yat-sen University, 132# Waihuan Dong Road, University City, Guangzhou 510006, China.

Tel.: +86 20 39943035; fax: +86 20 39943000.

E-mail addresses: frankwychen@yahoo.com (X. Chen), bihchang@mail.sysu.edu.cn (H.-c. Bi).

Table 1
Pharmacokinetic parameters of schisantherin A, schisandrin A,
schisandrol A and schisandrol B in WZ (0.25 g/kg) after an oral dose
to rats with or without an oral dose of Tacrolimus (FK506,1.89mg/kg).
Data are the mean [+ or -] SD (n = 5).

GROUPS                    Parameters of lignans in WZ

                   [C.sub.max](ng/ml)     [T.sub.max] (h)
Schisantherin A
  WZ alone         837.9 [+ or -] 79.0    5.35 [+ or -] 3.66
  +FK506           472.7 [+ or -] 184.6   3.30 [+ or -] 2.54

Schisandrin A
  WZ alone          17.1 [+ or -] 3.8     1.13 [+ or -] 0.48
  +FK506            15.9 [+ or -] 11.8    1.50 [+ or -] 1.45

Schisandrol A
  WZ alone          36.1 [+ or -] 11.8    3.60 [+ or -] 2.19
  +FK506            28.6 [+ or -] 10.5    1.50 [+ or -] 0.50

Schisandrol B
  WZ alone          13.8 [+ or -] 3.5     4.70 [+ or -] 3.70
  +FK506            9.7 [+ or -] 4.8      0.88 [+ or -] 1.02

GROUPS                     Parameters of lignans in WZ

                   [t.sub.1/2] (h)        MRT(h)
Schisantherin A
  WZ alone          2.79 [+ or -] 1.51    8.01 [+ or -] 1.10
  +FK506            7.28 [+ or -] 2.45    8.85 [+ or -] 1.50

Schisandrin A
  WZ alone          3.65 [+ or -] 0.94    4.33 [+ or -] 0.77
  +FK506            6.37 [+ or -] 3.33    7.00 [+ or -] 2.11

Schisandrol A
  WZ alone          3.51 [+ or -] 1.50    5.99 [+ or -] 0.44
  +FK506            3.73 [+ or -] 1.57    5.31 [+ or -] 1.74

Schisandrol B
  WZ alone          4.51 [+ or -] 1.75    8.62 [+ or -] 0.63
  +FK506           12.39 [+ or -] 7.09    8.42 [+ or -] 1.64

GROUPS             Parameters of lignans in WZ

                   [AUC.sub.0-24h] (ngh/ml)
Schisantherin A
  WZ alone         10,812.8 [+ or -] 2796.8
  +FK506             6980.6 [+ or -] 2935.6

Schisandrin A
  WZ alone           186.5 [+ or -] 95.0
  +FK506              88.0 [+ or -] 26.4

Schisandrol A
  WZ alone           297.1 [+ or -] 123.1
  +FK506             163,7 [+ or -] 72.7

Schisandrol B
  WZ alone           209.7 [+ or -] 63.0
  +FK506             120.4 [+ or -] 66.9

CROUPS             Parameters of lignans in WZ

                   [AUC.sub.0-[infinity]]
                   (ngh/ml)
Schisantherin A
  WZ alone         11,311.6 [+ or -] 2869.5
  +FK506             7156.0 [+ or -] 2992.7

Schisandrin A
  WZ alone            196.9 [+ or -] 97.6
  +FK506              110.5 [+ or -] 29.5

Schisandrol A
  WZ alone            329.7 [+ or -] 104.9
  +FK506              174.4 [+ or -] 76.5

Schisandrol B
  WZ alone            228.3 [+ or -] 73.4
  +FK506              176.3 [+ or -] 77.6

Table 2
Transport and permeability ratio of lignans (2 [micro]M) of WZ across
Caco-2 cell monolayers. Data are the mean [+ or -] SD (n = 3).

Lignans           Papp AP-BL
                  (x [10.sup.-6] cm/s)

Schisandrin A     24.86 [+ or -] 4.20
Schisandrin B      7.34 [+ or -] 1.94
Schisandrol A     17.97 [+ or -] 0.39
Schisandrol B     23.81 [+ or -] 3.93
Schisantherin A   34.41 [+ or -] 5.44

Lignans           Papp BL-AP (x 10-6 cm/s)  Transport ratio
                  (x [10.sup.-6] cm/s)      (BL-AP/AP-BL)

Schisandrin A     18.95 [+ or -] 4.72       0.76
Schisandrin B     13.38 [+ or -] 0.50       1.82
Schisandrol A     23.36 [+ or -] 1.13       1.30
Schisandrol B     22.77 [+ or -] 4.88       0.96
Schisantherin A   33.78 [+ or -] 4.84       0.98

Table 3
Effects of ketoconazole (10 [micro]M) on the metabolism of lignans in
WZ (0.1 [micro]M) in the human recombinant CYP 3A4 (12.5 pmol/ml).
Data are the mean [+ or -] SD. (n = 4).

Substrate          Without ketoconazole    With ketoconazole
                   Metabolized ratio (%)   Metabolized ratio (%)

Schisandrin A      93.5 [+ or -] 1.1       47.9 [+ or -] 6.0
Schisandrol A      57.3 [+ or -] 6.9       14.5 [+ or -] 10.1
Schisandrol B      71.1 [+ or -] 5.1       33.6 [+ or -] 10.1
Schisantherin A    31.3 [+ or -] 6.8       24.0 [+ or -] 3.7
FK506              22.6 [+ or -] 3.2       --

Substrate          P

Schisandrin A      <0.0001
Schisandrol A      0.0004
Schisandrol B      0.0006
Schisantherin A    0.11
FK506

--, the metabolism of FK506 was completely inhibited by ketocanazole
in rCYP 3A4 system.

Table 4
Effects of ketoconazole (10 [micro]M) on the metabolism of lignans in
WZ(0.1 [micro]M) in the human recombinant CYP 3A5 (12.5 pmol/ml). Data
are the mean [+ or -]SD. (n = 4).

Substrate          Without ketoconazole     With ketoconazole
                   Metabolized ratio (%)    Metabolized ratio (%)

Schisandrin A      58.5 [+ or -] 6.1        --
SchisandrolA       24.9 [+ or -] 8.6        --
Schisandrol B      37.4 [+ or -] 20.3        0.5 [+ or -] 3.3
Schisantherin A    --                       --
FK506              33.4 [+ or -] 4.0        16.1 [+ or -] 4.4

Substrate          P

Schisandrin A
SchisandrolA
Schisandrol B      0.01
Schisantherin A
FK506              0.0009

--, the metabolism of lignans in WZ was completely inhibited by
ketocanazole in rCYP 3A5 system.

Table 5
Km ([micro]M) for the enzymatic reactions of the lignans in WZ and
FK506 (n=4).

Substrate         CYP3A4               CYP3A5
                  Km ([micro]M)        Km ([micro]M)

Schisandrin A     0.064                0.050
Schisandrol A     0.072                0.068
Schisandrol B     2.0 x [10.sup.-6]    0.005
FK506             0.11                 0.24
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Author:Qin, Xiao-ling; Chen, Xiao; Zhong, Guo-ping; Fan, Xiao-mei; Wang, Ying; Xue, Xin- ping; Huang, Min;
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Date:Apr 15, 2014
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