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At least 19 recordsLinked to original sources
PubMed1994

Plasma concentrations of free and conjugated silybin after oral intake of a silybin-phosphatidylcholine complex (silipide) in healthy volunteers.

The plasma concentrations of free (unconjugated) and conjugated silybin after intake of a single oral dose of a lipophilic silybin-phospatidylcholine complex (silipide, 80 mg expressed as silybin equivalents) were evaluated in 12 healthy volunteers by using a sensitive and specific HPLC method. Free silybin concentrations reached a peak of 141 +/- 31 ng/ml (mean +/- SEM) at 2.4 hours after dosing and declined thereafter with a half-life of about 2 hours. Peak concentrations of conjugated silybin were greater (255 +/- 35 ng/ml) and occurred at a later time (about 3.8 hours). The elimination of conjugated drug tended to be slower than that of free drug. AUC values for conjugated sylibin were about three-fold greater than those of free drug. It is concluded that after oral intake of silipide, silybin undergoes extensive conversion to conjugated derivative(s) which are retained in the circulation at relatively large concentrations.

Administration, Oral↗
PubMed2003

Molecular structure and stereochemistry of silybin A, silybin B, isosilybin A, and isosilybin B, Isolated from Silybum marianum (milk thistle).

Two pairs of diastereoisomeric flavonolignans, silybin A, silybin B, isosilybin A, and isosilybin B, were successfully separated from Silybum marianum by sequential silica gel column chromatography, preparative reversed-phase HPLC, and recrystallization. Complete stereochemical assignments at C-2, C-3, C-7', and C-8' of these flavonolignans have been achieved. On the basis of X-ray crystallographic analysis and optical rotation data, coupled with comprehensive (1)H and (13)C NMR spectral data interpretation including COSY, HMQC, and HMBC, the stereochemistry of these diastereoisomers was determined unambiguously as silybin A (4), 2R, 3R, 7'R, 8'R; silybin B (5), 2R, 3R, 7'S, 8'S; isosilybin A (6), 2R, 3R, 7'R, 8'R; and isosilybin B (7), 2R, 3R, 7'S, 8'S.

Drugs, Chinese Herbal↗
PubMed1980

[Mechanism of silybin action, III. Resorption of the flavonolignane derivative silybin into rat liver cells (author's transl)].

After tritium labelling of silybin the time-dependent uptake of the flavonolignane derivative into rat liver was measured. Within the liver cells the distribution of silybin (and -metabolites) in cytosol, nuclear constituents and membrane material was determined and the accumulation of the flavonolignane derivative in cytosol and nuclear membranes confirmed by autoradiography. Within the nuclei a preferential binding on chromosomal proteins was found.

Animals↗
PubMed2005

The preparation of silybin-phospholipid complex and the study on its pharmacokinetics in rats.

The aim of the present study was to find a way of prepare silybin-phospholipid complex to make oral bioavailability of silybin increase and to study its physicochemical properties and to compare the pharmacokinetic characteristics and bioavailability after oral administration of silybin-phospholipid complex and silybin-N-methylglucamine in rats. Using ethanol as a reaction medium, silybin and phospholipids were resolved into the medium, after the organic solvent was removed under vacuum condition, silybin-phospholipid complex was formed. The new complex's physicochemical properties including scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), solubility, dissolution, etc., were tested. The concentrations of silybin after oral administration of silybin-phospholipid complex and silybin-N-methylglucamine at different time in rats were determined by RP-HPLC. The pharmacokinetic parameters were computed by software program 3p97. Our data showed that silybin and phospholipids in the silybin-phospholipid complex were combined by non-covalent-bond, not forming a new compound and the solubility of silybin-phospholipid complex in water and in n-octanol was effectively enhanced. We found that mean plasma concentration-time curve of silybin after oral administration of silybin-phospholipid complex and silybin-N-methylglucamine in rats was both in accordance with open single-compartment model with first-order absorption. Pharmacokinetic parameters of silybin in rats were Tmax 10 and 5 min; Cmax 126.72 and 104.29 ng ml(-1); AUC(0-infinity) 1020.33 and 235.81 ng ml(-1)h, respectively. The bioavailability of silybin in rats was increased remarkably after oral administration of silybin-phospholipid complex comparing to silybin-N-methylglucamine. This was mainly due to an impressive improvement of the lipophilic property of silybin-phospholipid complex and improvement of the biological effect of silybin.

Administration, Oral↗
PubMed2005

[Preparation of silybin-phospholipid complex and its bioavailability in rats].

AIM: To prepare silybin-phospholipid complex and study its physicochemical properties. To compare the pharmacokinetic characteristics and bioavailability after oral administration of silybinphospholipid complex and silybin material in rats. METHODS: Using acetone as a reaction medium, silybin and phospholipid were resolved into the medium, when the organic solvent was clear, then removed under vacuum evaporation, silybin-phospholipid complex was obtained. The new complex' s physicochemical properties including DSC, UV, IR were determined. The concentrations of non-conjugated and total silybin after oral administration of silybin-phospholipid complex and silybin material at different time in rats were determined by RP-HPLC. The pharmacokinetic parameters were computed by software program 3P97. RESULTS: Experiment results showed that silybin and phospholipid in the silybin-phospholipid complex were combined by non-covalent-bond, not forming a new compound and the solubility of silybin-phospholipid complex in water and n-octanol was effectively enhanced. It was found that mean plasma concentration-time curve of silybin after oral administration of silybin-phospholipid complex in rats was in accordance with one-compartment model with first-order absorption. Pharmacokinetic parameters of non-conjugated and total silybin in rats were respectively T(max) 10 min and 2 h; C(max) 0.11 and 1.08 microg x mL(-1); T1/2 2.18 and 3.84 h; AUC(0-infinity) 1.71 and 12.94 microg x mL(-1) x h. However, after oral administration of silybin material, plasma levels of both non-conjugated and total silybin were within the analytical detection limit. CONCLUSION: It was concluded that after oral administration of silybin-phospholipid complex in rats the bioavailability of silybin increased greatly. This was mainly due to an obvious improvement of the lipophilic property of silybin-phospholipid complex compared with silybin material and an increase in gastrointestinal absorption.

Administration, Oral↗
PubMed1996

Antiproliferative effect of silybin on gynaecological malignancies: synergism with cisplatin and doxorubicin.

The aim of this study was to test the antiproliferative activity of silybin, a flavonoid, on human ovarian and breast cancer cell lines. Since flavonoids are thought to act through Type II oestrogen binding sites (Type II EBS), silybin binding to Type II EBS was also examined. Silybin, used in concentrations from 0.1 to 20 microM, exerted a dose-dependent growth inhibitory effect on OVCA 433, A2780 parental and drug-resistant ovarian cancer cells, and MCF-7 doxorubicin (DOX)-resistant breast cancer cells (IC50 = 4.8-24 microM). Both L and D diastereoisomers of silybin were effective in inhibiting A2780 WT cell growth (IC50 = 14 and 20 microM, respectively). Flow cytometry revealed that silybin decreased the percentage of cells in the S and G2-M phases of the cell cycle with a concomitant increase in cells in the G0-G1 phase. Silybin was able to compete with [3H]E2 for nuclear but not cytosolic Type II EBS. Its affinity parallels its efficacy in inhibiting cell proliferation. Furthermore, silybin (0.1 and 1 microM) potentiates the effect of cisplatin (CDDP) (0.1-1 micrograms/ml) in inhibiting A2780 WT and CDDP-resistant cell growth. Similar results were obtained on MCF-7 DOX-resistant cells when silybin (0.1 microM) was associated with doxorubicin (0.1-10 micrograms/ml). As assessed by the Berembaum isobole method, the effect of silybin-CDDP and silybin-DOX combinations results in a synergistic action. Using the 'stem cell assay' described by Hamburger and Salmon [Science 1977, 197, 461-463], we found that silybin exerted a dose-dependent inhibition of clonogenic efficiency of cells derived from three ovarian tumours (IC50 = 7.4, 4 and 6.4 microM, respectively). Since CDDP and DOX are the two most commonly used drugs for gynaecological tumours, the clinical application of silybin is currently under investigation in our institute.

Antineoplastic Agents↗
PubMedDate not supplied

Pharmacokinetic studies on IdB 1016, a silybin- phosphatidylcholine complex, in healthy human subjects.

IdB 1016 is a complex of silybin (the main active component of silymarin) and phosphatidylcholine, which in animal models shows greater oral bioavailability and therefore greater pharmacological activity compared with pure silybin and silymarin. In order to assess its pharmacokinetic profile in man, plasma silybin levels were determined after administration of single oral doses of IdB 1016 and silymarin (equivalent to 360 mg silybin) to 9 healthy volunteers. Although absorption was rapid with both preparations, the bioavailability of IdB 1016 was much greater than that of silymarin, as indicated by higher plasma silybin levels at all sampling times after intake of the complex. Regardless of the preparation used, the terminal half-life was relatively short (generally less than 4 h). In a subsequent study, 9 healthy volunteers received IdB 1016 (120 mg b.i.d., expressed as silybin equivalents) for 8 consecutive days. The plasma silybin level profiles and kinetic parameters on day 1 were similar to those determined on day 8. Most of the silybin present in the systemic circulation was in conjugated form. Less than 3% of the administered dose was accounted for by urinary recovery of free plus conjugated silybin, a significant proportion of the dose probably being excreted in the bile. It is concluded that complexation with phosphatidylcholine in IdB 1016 greatly increases the oral bioavailability of silybin, probably by facilitating its passage across the gastrointestinal mucosa.

Administration, Oral↗
PubMed1979

[Influence of Silybin-dihemisuccinate on fatty acid synthesis in rat liver (author's transl)].

1. The influence of silybin-dihemisuccinate, a derivative of the flavonolignane silybin from silybum marianum L. Gaertn., on fatty acid biosynthesis of rat liver was studied measuring the radioactivity incorporation of [1-14C]-acetate and 3H2O in fatty acids of the postmitochondrial supernatant of liver homogenates and in fatty acids of liver slices as well as the activities of enzymes involved in do novo synthesis of fatty acids. 2. In the postmitochondrial supernatant of liver homogenates or in liver slices, prepared 30 or 60 min after i.v. injection of 150.6 mg/kg silybin-dihemisuccinate, radioactivity incorporation of 14C-acetate or 3H2O in fatty acids was lowered by about 25%. Adding silybin-dihemisuccinate to incubation mixture in vitro in the concentration of 0.45--0.6 mmol/l silybin the radioactivity incorporation was linearly diminished with increased concentration of silybin. 3. After in vitro addition of varying concentrations of silybin to incubation mixtures in the presence of 0.1 mmol/l silybin activities of acetyl-CoA-carboxylase, fatty-acid-synthetase and ATP-citrate-lyase were diminished by about 50%, while activity of NADP-malate-dehydrogenase was lowered by 20% in the presence of 1 mmol/l silybin. 4. Our results suggest that silybin caused an unspecific and, under in vivo conditions, transitory inhibition of fatty acid synthesis in rat liver.

ATP Citrate (pro-S)-Lyase↗
PubMed2005

Effect of silybin and its glycosides on the expression of cytochromes P450 1A2 and 3A4 in primary cultures of human hepatocytes.

Four beta-glycosides of flavonoligan silybin, i.e. silybin beta-galactoside, silybin beta-glucoside, silybin beta-maltoside, silybin beta-lactoside were synthesized in order to improve silybin water solubility and bioavailability (Kren et al., J Chem Soc, Perkin Trans 1, 2467-2474, 1997). The presented paper deals with the effect of silybin and its synthetic beta-glycosides on the expression of two major cytochrome P450 isoforms, CYP1A2 and CYP3A4. Primary cultures of human hepatocytes were the model of choice. mRNAs were analyzed using Northern blot and P-radiolabelled probes. CYP protein content was determined by immunoblotting using specific antibodies. Silybin and its beta-glycosides do not induce expression of CYP1A2 and CYP3A4. Tested compounds did not affect inducible expression of CYP1A2 and CYP3A4 by dioxin and rifampicin, respectively, as evaluated at the level of mRNAs and proteins. Silybin and its beta-glycosides do not interfere with the expression of CYP1A2 and CYP3A4, are not likely to produce drug-drug interactions in terms of the inducibility of two important cytochromes P450.

Aryl Hydrocarbon Hydroxylases↗
PubMed2004

Stereoselective metabolism of silybin diastereoisomers in the glucuronidation process.

A separation method for the hepatoprotective drug silybin and its metabolites by RP-HPLC was described. Based on this separation, the stereoselectivity of the metabolism of silybin was investigated by incubation of the drug and its two diastereoisomers with bovine liver microsomes. Information about the structures of these metabolites was obtained, using UV, HPLC/MS and NMR spectra. Four major metabolites (M(1), M(4) of silybin A and M(2), M(5) of silybin B), were prepared by preparative HPLC, and their configurations were accomplished by NMR spectra. A HPLC method was used to quantify the metabolites. The results showed that silybin was extensively metabolized and the major sites for glucuronidation were the C-20, C-7, at phenolic OH groups. Furthermore, the results obtained reveal that there was significant stereoselectivity in the glucuronidation process of silybin. Silybin B was glucuronidated at a more efficient rate than its diastereoisomer, and glucuronidation of silybin B was much preferred at the 20 position, while that of silybin A was similar at both 7 and 20 position.

Glucuronides↗
PubMed1992

Pharmacokinetics of silybin in bile following administration of silipide and silymarin in cholecystectomy patients.

The biliary excretion of silybin, the main active component of silymarin, was evaluated by using a specific HPLC method in 9 cholecystectomy patients with T-tube drainage following single oral doses of silipide (CAS 134499-06-2), a lipophilic silybin-phosphatidylcholine complex (IdB 1016), and of silymarin (120 mg, expressed as silybin equivalents). After intake of silipide, the concentration of silybin in bile reached a peak within 4 h and declined thereafter with a mean time of about 10 h. After administration of silymarin, biliary silybin concentrations were several-fold lower than those observed after intake of silipide. The bile collected after silymarin intake also contained considerable amounts of isosilybin (a silybin isomer) and very low levels of silydianin and silycristin. The amount of silybin recovered in bile in free and conjugated form within 48 h accounted for 11% of the dose after silipide and for 3% of the dose after silymarin. Plasma silybin concentrations, determined in 3 subjects, were several-fold lower than those in bile after intake of silipide and mostly undetectable after intake of silymarin. These data indicate that the bioavailability of silybin is much greater after administration of silipide than after administration of silymarin. This results in increased delivery of the compound to the liver, which represents the target organ for pharmacological action.

Adult↗
PubMed1988

Modulation of human polymorphonuclear leukocyte function by the flavonoid silybin.

The effect in vitro of the naturally occurring flavonoid silybin on human polymorphonuclear leukocyte (PMN) functions has been studied. Preincubation of PMNs for 10 min at 37 degrees C with silybin inhibited, in a dose-dependent way, the luminol-enhanced chemiluminescence (CL) generated by stimulated cells without affecting the non-enhanced CL or superoxide anion production evaluated by the cytochrome C reduction assay. No significant effect of silybin on PMN phagocytic or chemotactic activities were found. Silybin did not absorb light at the wavelength of luminol-enhanced CL and was not toxic to PMNs at the concentrations used. Catalase, a scavenger of H2O2, inhibited luminol-enhanced CL to a similar degree as silybin; moreover, when incubated together with PMNs, silybin and catalase did not produce an additive inhibition of CL. On the contrary, the simultaneous addition of silybin and sodium azide, an inhibitor of myeloperoxidase, further increased inhibition over that seen with azide alone. These results suggest that inhibition of H2O2 may be the mechanism by which silybin inhibits the luminol-enhanced CL generated by stimulated PMNs. Such results indicate a possible anti-inflammatory activity for silybin even if their clinical relevance remains to be elucidated.

Azides↗
PubMed1994

Pharmacokinetics of silybin following oral administration of silipide in patients with extrahepatic biliary obstruction.

The pharmacokinetics of silybin, the main active component of silymarin, following administration of a lipophilic silybin-phosphatidylcholine complex (silipide) was evaluated in fourteen patients with cholestasis secondary to biliary extrahepatic obstruction. Each patient received a single oral dose of silipide (120 mg, expressed as silybin equivalents). Blood samples for high performance liquid chromatography (HPLC) determination of free (unconjugated) and total (free+conjugated) silybin were collected at frequent intervals for up to 24 h after dosing. Absorption from the gastrointestinal tract occurred rapidly, peak concentrations of free drug being observed within 3 h in most patients. Thereafter, the decline in plasma free silybin levels was relatively rapid, and at 12 h the concentration of free drug had already approached the limit of quantitation (2 ng/ml). At all sampling times, the total (free+conjugated) concentration was much higher than the free concentration. Total silybin levels reached a peak at about 3 to 4 h and persisted at relatively high values (> or = 400 ng/ml) throughout the entire sampling period. On average, the area under the curve for total silybin was more than 40-fold greater than the area under the curve for free silybin. These data suggest that extrahepatic biliary obstruction is associated with a reduced clearance of conjugated silybin, probably due to impaired excretion of the conjugate in bile.

Adult↗
PubMed2004

Effect of silybin on phorbol myristate actetate-induced protein kinase C translocation, NADPH oxidase activity and apoptosis in human neutrophils.

Mechanism of the action of silybin (1) and its derivatives (2-4), possessing different lipid solubility in PMA-stimulated neutrophils was evaluated. Silybin (1) inhibited the calcium, phosphatidylserine- and diacylglycerol-dependent protein kinase C translocation and the NADPH oxidase activity in PMA-stimulated neutrophils and resulted in decreased apoptosis. Furthermore, silybin (1) inhibited xanthine oxidase activity and hem-mediated oxidative degradation of low-density lipoprotein, as well. Its derivatives (2-4), possessing different lipid-solubility, affected all the studied parameters. The lipid solubility of silybin (1) was enhanced by methylation (5'7'4''trimethylsilybin: 2), whereas a decrease in lipid-solubility by acetylation of compound 2 (5',7,'4"-trimethylsilybin-acetate: 3) or all the hydroxyl groups of silybin (peracetyl-silybin: 4) attenuated the antioxidant capacity by decreasing the inhibition in PKC translocation and NADPH oxidase activation. All the derivatives of silybin (2-4) showed no inhibition in cell free systems; e.g. did not alter the xanthine oxidase activity and the hem-mediated oxidative degradation of LDL. In conclusion, the antioxidant activity of (1) might be due to its ability to inhibit PKC translocation and NADPH oxidase activation in PMA-stimulated neutrophils. The increase of lipid solubility of silybin (1) supports its penetration through cell membrane and enhances its inhibitory effects. This structural modification of (1) might have pharmacological consequences.

Antioxidants↗
PubMed2002

Antioxidant properties of silybin glycosides.

New soluble derivatives of the hepatoprotective flavonolignan silybin (1), namely silybin galactoside (2), glucoside (3), lactoside (4) and maltoside (5) were investigated for their radical scavenging and antilipoperoxidation properties. According to cyclic voltammetry the results show that glycosides are weaker electron donors than silybin, although it was of interest that they were found to be more potent scavengers of the 1,1-diphenyl-2-picrylhydrazyl and the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)-derived radicals. The glycosides (2)-(5) were more efficient than silybin in preventing tert-butylhydroperoxide-induced lipoperoxidation of rat liver mitochondrial membranes. Furthermore, glycosides (2)-(5) were significantly more cytoprotective than silybin in tert-butylhydroperoxide-damaged rat erythrocytes and primary hepatocyte cultures. Glycosylation of silybin substantially reduced its toxic effects in primary cultured hepatocytes observed during prolonged incubation. These results suggest that silybin glycosides are suitable soluble derivatives of silybin for experimental studies and may have therapeutic potential.

Animals↗
PubMed1975

[Studies of the metabolism and excretion of silybin in the rat].

The metabolism and excretion of silybin (as N-methyl-glucamine salt) was investigated after intravenous and oral administration to rats. In the urine, silybin was excreted mostly in the unchanged form after intravenous as well as oral application, whilst in the bile it appeared above all in the form of metabolites. By hydrolysis with arylsulfatase/beta-glucuronidase, the metabolites were identified as sulfate and glucuronide conjugates of silybin and dehyrosilybin; the latter appeared in small quantities as a dehydrated product of silybin. After intravenous injection of 20 mg silybin per kg body weight, the excreted amount of silybin after 48 h was 8%, whereas 76% was eliminated in the bile within the same period of time. After oral application of 2--20 mg silybin/kg body weight 20% after 40 mg/kg 35% and after 120 mg/kg 20% of the administered silybin was excreted in the bile during 48 h. The maximum excretion rate was achieved at application of 20 mg/kg p.o. after 1 h. At this dosage, 2--5% was eliminated within the same time in the urine. The excretion of silybin mainly took place (more than 80% of the total of excreted bilybin) in the bile, both after oral and intravenous administration.

Administration, Oral↗