Complete Isolation and Characterization of Silybins and Isosilybins from Milk Thistle (Silybum marianum).

Kim, Nam‐Cheol; Graf, Tyler N.; Sparacino, Charles; Wani, Mansukh C.; Wall, Monroe E.

doi:10.1002/chin.200338195

Cited by 79 publications

(106 citation statements)

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“…4) (Fig. 4) were in agreement with those in published literature (Kim et al, 2003;Lee and Liu, 2003;Lee et al, 2006). Quantification of the six silymarin flavonolignans in human plasma was performed with LC-ESI-MS with a SIM detection at m/z 481 in the negative ion mode, which has higher sensitivity than in the positive ion mode.…”

Section: Estimation Of Silymarin Flavonolignans In Milksupporting

confidence: 79%

Pharmacokinetics and Metabolic Profile of Free, Conjugated, and Total Silymarin Flavonolignans in Human Plasma after Oral Administration of Milk Thistle Extract

Zhao

Dumas

Schrieber³

et al. 2007

Drug Metab Dispos

156

157

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ABSTRACT:Silymarin, a mixture of polyphenolic flavonoids extracted from milk thistle (Silybum marianum), is composed mainly of silychristin, silydianin, silybin A, silybin B (SB B ), isosilybin A (ISB A ), and isosilybin B. In this study, the plasma concentrations of free (unconjugated), conjugated (sulfated and glucuronidated), and total (free and conjugated) silymarin flavonolignans were measured using liquid chromatography-electrospray ionization-mass spectrometry, after a single oral dose of 600 mg of standardized milk thistle extracts to three healthy volunteers. Pharmacokinetic analysis indicated that silymarin flavonolignans were rapidly eliminated with short half-lives (1-3 and 3-8 h for free and conjugated, respectively). The AUC 03ؕ values of the conjugated silymarin flavonolignans were 4-to 30-fold higher than those of their free fractions, with SB B (mean AUC 03ؕ ‫؍‬ 51 and 597 g ⅐ h/l for free and conjugated, respectively) and ISB A (mean AUC 03ؕ ‫؍‬ 30 and 734 g ⅐ h/l for free and conjugated, respectively) exhibiting higher AUC 03ؕ values in comparison with other flavonolignans. Near the plasma peak times (1-3 h), the free, sulfated, and glucuronidated flavonolignans represented approximately 17, 28, and 55% of the total silymarin, respectively. In addition, the individual silymarin flavonolignans exhibited quite different plasma profiles for both the free and conjugated fractions. These data suggest that, after oral administration, silymarin flavonolignans are quickly metabolized to their conjugates, primarily forming glucuronides, and the conjugates are primary components present in human plasma.

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Section: Estimation Of Silymarin Flavonolignans In Milksupporting

confidence: 79%

Pharmacokinetics and Metabolic Profile of Free, Conjugated, and Total Silymarin Flavonolignans in Human Plasma after Oral Administration of Milk Thistle Extract

Zhao

Dumas

Schrieber³

et al. 2007

Drug Metab Dispos

156

157

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“…As milk thistle extracts prove increasingly useful in preclinical studies, progression to clinical studies will require complete and precise chemical characterization of study materials. As members of our research group were the first to purify milligram quantities of all 7 milk thistle flavonolignan compounds for biological studies, 6 we hope to answer the call of our colleagues in promoting clarity in the nomenclature of biologically active compounds derived from milk thistle. Table 1 contains a quick glossary of terms used to describe milk thistle components in the literature, often interchangeably and, unfortunately, incorrectly.…”

Section: Nomenclature Of Milk Thistle Compoundsmentioning

confidence: 99%

“…7,8 Although many studies were conducted over the ensuing 3 decades, the Research Triangle Institute Natural Products Laboratory first reported on the resolution and purification of all 7 flavonolignans from this mixture (Figure 1). 6 What was first termed silybin can be resolved into 2 diastereoisomers, silybin A and silybin B. A similar diastereoisomeric mixture exists, yielding isosilybin A and isosilybin B (which are regioisomers of silybin A and silybin B).…”

Section: Nomenclature Of Milk Thistle Compoundsmentioning

confidence: 99%

“…Silymarin is simply the initial extract of milk thistle seeds made with ethanol (or other solvents 10,11 ) that contains 65% to 80% total flavonolignans and a small amount of a flavonoid (taxifolin, barely discernable in the HPLC chromatogram of silymarin) (Figure 2), with the remainder containing fatty acids and polyphenolic compounds. 1,6,12 The most commonly cited silymarin product used in clinical trials is Legalon, or Thisilyn in The most common class of compound present in milk thistle extract. Milk thistle flavonolignans result from a peroxidase reaction in the plant that fuses the flavonoid, taxifolin (known also as dihydroquercetin), with coniferyl alcohol, resulting in at least 7 compounds that all share the formula weight of 482.1.…”

Section: Nomenclature Of Milk Thistle Compoundsmentioning

confidence: 99%

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Milk Thistle Nomenclature: Why It Matters in Cancer Research and Pharmacokinetic Studies

2007

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Extracts of milk thistle have been recognized for centuries as "liver tonics" and are well-known to prevent or reverse hepatotoxicity of reactive drug metabolites or naturally occurring toxins. Milk thistle extracts are now under intense study in the experimental therapeutics of cancer for chemoprevention, treatment, and amelioration of chemotherapy side effects. Precision in nomenclature, however, has lagged behind this progress. The crude commercial product of milk thistle is termed silymarin, a complex of at least 7 flavonolignans and 1 flavonoid that comprises 65% to 80% of milk thistle extract. From silymarin is derived silibinin, a semipurified fraction once thought to be a single compound but now recognized as a 1:1 mixture of 2 diastereoisomers, silybin A and silybin B. The distinction between silymarin and silibinin is not only important to understanding the historical literature, but thorough characterization and use of chemically defined mixtures in preclinical and clinical studies are essential to the progress of these botanical compounds as human therapeutics. As a result, we urge clinicians and preclinical investigators alike to exercise rigor in nomenclature and use pure compounds or precisely defined chemical mixtures in subsequent studies. Herein, we provide a guide to the proper nomenclature and composition of milk thistle extracts and discuss the known pharmacokinetic studies of these botanical medicines. The druginteraction potential of these extracts appears to be quite low, and in fact, silibinin appears to synergize with the antitumor effects of some commonly used chemotherapeutics. However, some precautions are advised as highdose, phase II studies are conducted.

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“…Derived from the milk thistle plant Silybum marianum, silymarin is a complex mixture of six major flavonolignans (silybins A and B, isosilybins A and B, silychristin, and silydianin), as well as other minor polyphenolic compounds (Kim et al, 2003). Silymarin has been shown to have antioxidant, anti-inflammatory/ immunomodulatory, and antifibrotic properties in various in vitro and animal models (Abenavoli et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Differences in the Disposition of Silymarin between Patients with Nonalcoholic Fatty Liver Disease and Chronic Hepatitis C

Schrieber¹,

Hawke²,

Zhao³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Silymarin, derived from the milk thistle plant Silybum marianum and widely used for self-treatment of liver diseases, is composed of six major flavonolignans including silybin A and silybin B, which are the predominant flavonolignans quantified in human plasma. The single-and multiple-dose pharmacokinetics of silymarin flavonolignans were examined in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis C virus (HCV) to determine whether the disposition of silymarin and therefore its potential efficacy vary among liver disease populations. Cohorts of eight subjects with noncirrhotic liver disease were randomized 3:1 to oral silymarin or placebo (280 or 560 mg) every 8 h for 7 days. Forty-eight-hour blood sampling was conducted after the first and final doses. In general, plasma concentrations of silybin A and silybin B were higher, whereas concentrations of conjugates were lower in NAFLD compared with HCV. After adjustment of the area under plasma concentration-time curve from 0 to 8 h (AUC 0-8 h ) for weight and dose, only silybin B and silybin B conjugates differed significantly between disease types. For NAFLD, the adjusted mean AUC 0-8 h was higher for silybin B (p < 0.05) but lower for silybin B conjugates (p < 0.05) compared with that for HCV. At the 280-mg dose, steady-state plasma concentrations of silybin B conjugates for NAFLD subjects were characterized by 46% lower AUC 0-8 h (p < 0.05) and 42% lower C max (p < 0.05) compared with HCV subjects. Evidence of enterohepatic cycling of flavonolignans was only observed in NAFLD subjects. In summary, the efficacy of silymarin may be more readily observed in NAFLD patients because of their higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared with those in HCV patients.

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Complete Isolation and Characterization of Silybins and Isosilybins from Milk Thistle (Silybum marianum).

Cited by 79 publications

References 1 publication

Pharmacokinetics and Metabolic Profile of Free, Conjugated, and Total Silymarin Flavonolignans in Human Plasma after Oral Administration of Milk Thistle Extract

Pharmacokinetics and Metabolic Profile of Free, Conjugated, and Total Silymarin Flavonolignans in Human Plasma after Oral Administration of Milk Thistle Extract

Milk Thistle Nomenclature: Why It Matters in Cancer Research and Pharmacokinetic Studies

Differences in the Disposition of Silymarin between Patients with Nonalcoholic Fatty Liver Disease and Chronic Hepatitis C

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