The Effects of Milk Thistle (<i>Silybum marianum</i>) on Human Cytochrome P450 Activity

Kawaguchi‐Suzuki, Marina; Frye, Reginald F.; Zhu, Hao; Brinda, Bryan J.; Chavin, Kenneth D.; Bernstein, Hilary J.; Markowitz, John S.

doi:10.1124/dmd.114.057232

Cited by 50 publications

(30 citation statements)

References 39 publications

(61 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The results of experiments on blood and urine collected in Days 0, 10, and 27 indicated that silymarin did not have toxicity (Valentová et al, ). In another trial on healthy people, oral intake of capsules containing 175 mg of milk thistle extract or 140‐mg silymarin three times a day for 14 days had no major toxicity, and no adverse reactions were observed (Kawaguchi‐Suzuki et al, ).…”

Section: Safety and Adverse Reactions Of Oral Silymarin In Humansmentioning

confidence: 99%

Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review

Soleimani

Delghandi

Moallem

et al. 2019

Phytotherapy Research

153

View full text Add to dashboard Cite

Milk thistle (Silybum marianum) is a medicinal plant from the Asteraceae family. Silymarin is the major constituent of milk thistle extract and is a mixture of some flavonolignans such as silybin, which is the most active component of silymarin. It is most commonly known for its hepatoprotective effect. Also, studies have shown other therapeutic effects such as anticancer, anti‐Alzheimer, anti‐Parkinson, and anti‐diabetic, so its safety is very important. It has no major toxicity in animals. Silymarin was mutagen in Salmonella typhimurium strains in the presence of metabolic enzymes. Silybin, silydianin, and silychristin were not cytotoxic and genotoxic at concentration of 100 μM. Silymarin is safe in humans at therapeutic doses and is well tolerated even at a high dose of 700 mg three times a day for 24 weeks. Some gastrointestinal discomforts occurred like nausea and diarrhea. One clinical trial showed silymarin is safe in pregnancy, and there were no anomalies. Consequently, caution should be exercised during pregnancy, and more studies are needed especially in humans. Silymarin has low‐drug interactions, and it does not have major effects on cytochromes P‐450. Some studies demonstrated that the use of silymarin must be with caution when co‐administered with narrow therapeutic window drugs.

show abstract

Section: Safety and Adverse Reactions Of Oral Silymarin In Humansmentioning

confidence: 99%

Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review

Soleimani

Delghandi

Moallem

et al. 2019

Phytotherapy Research

153

View full text Add to dashboard Cite

show abstract

“…To our knowledge, no clinical evidence has confirmed the significant metabolic interaction involving CYP2C9. Additionally, our group determined that the MT supplement Legalon ® had no significant effect upon TOLB pharmacokinetics when administered to healthy volunteers (Kawaguchi-Suzuki et al, 2014). In accordance with these clinical observations, our ex vivo model showed no significant inhibition by MT on human CYP2C9 ( Figure 1 ), even when samples contained relatively high plasma concentrations of silybin A and B ( Table 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…Potentially significant inhibition of CYP2C9, 3A and major hepatic UDP-glucuronosyltransferases (UGTs) by silymarin components have been reported in several in vitro studies (Beckmann-Knopp et al, 2000; Brantley et al, 2010; Doehmer et al, 2011; Sridar et al, 2004). However, most clinical BDI investigations have failed to confirm any clinically relevant BDI (Gurley et al, 2004; Kawaguchi-Suzuki et al, 2014; Rajnarayana et al, 2004). …”

Section: Introductionmentioning

confidence: 99%

An ex vivo approach to botanical–drug interactions: A proof of concept study

Wang

Zhu

Munoz

et al. 2015

Journal of Ethnopharmacology

Self Cite

View full text Add to dashboard Cite

Ethnopharmacological relevance Botanical medicines are frequently used in combination with therapeutic drugs, imposing a risk for harmful botanical-drug interactions (BDIs). Among the existing BDI evaluation methods, clinical studies are the most desirable, but due to their expense and protracted time-line for completion, conventional in vitro methodologies remain the most frequently used BDI assessment tools. However, many predictions generated from in vitro studies are inconsistent with clinical findings. Accordingly, the present study aimed to develop a novel ex vivo approach for BDI assessment and expand the safety evaluation methodoloy in applied ethnopharmacological research. Materials and Methods This approach differs from conventional in vitro methods in that rather than botanical extracts or individual phytochemicals being prepared in artificial buffers, human plasma/serum collected from a limited number of subjects administered botanical supplements was utilized to assess BDIs. To validate the methodology, human plasma/serum samples collected from healthy subjects administered either milk thistle or goldenseal extracts were utilized in incubation studies to determine their potential inhibitory effects on CYP2C9 and CYP3A4/5, respectively. Silybin A and B, two principal milk thistle phytochemicals, and hydrastine and berberine, the purported active constituents in goldenseal, were evaluated in both phosphate buffer and human plasma based in vitro incubation systems. Results Ex vivo study results were consistent with formal clinical study findings for the effect of milk thistle on the disposition of tolbutamide, a CYP2C9 substrate, and for goldenseal’s influence on the pharmacokinetics of midazolam, a widely accepted CYP3A4/5 substrate. Compared to conventional in vitro BDI methodologies of assessment, the introduction of human plasma into the in vitro study model changed the observed inhibitory effect of silybinA, silybin B and hydrastine and berberine on CYP2C9 and CYP3A4/5, respectively, results which more closely mirrored those generated in clinical study. Conclusions Data from conventional buffer-based in vitro studies were less predictive than the ex vivo assessments. Thus, this novel ex vivo approach may be more effective at predicting clinically relevant BDIs than conventional in vitro methods.

show abstract

“…The pharmacokinetic parameter endpoints AUC last , AUC ∞ , and C max for midazolam and 1′‐hydroxymidazolam were evaluated using the standard bioequivalence approach in which the absence of a clinically relevant interaction was concluded if the 90% confidence interval (CI) for the geometric mean ratio (GMR) was not contained within the no‐effect bounds of 80% to 125% . Based on an intrasubject variation of 17% for midazolam AUC, a sample size of 12 subjects would provide at least 80% power to demonstrate that the 90%CI of the geometric mean ratio would fall within the no‐effect range of 80% to 125%. SAS version 9.3 was used for analysis (SAS Institute Inc, Cary, North Carolina).…”

Section: Methodsmentioning

confidence: 99%

Effect of Low‐Furanocoumarin Hybrid Grapefruit Juice Consumption on Midazolam Pharmacokinetics

Kawaguchi‐Suzuki

Nasiri‐Kenari

Shuster

et al. 2016

The Journal of Clinical Pharma

Self Cite

View full text Add to dashboard Cite

The objectives of this study were to investigate the effect of grapefruit juice low in furanocoumarins on CYP3A activity and to summarize previous findings of enzyme inhibition measured by the metabolism of midazolam after intake of grapefruit juice. Twelve healthy volunteers participated in a prospective, randomized, double-blinded, three-way crossover clinical study to determine the effect of regular grapefruit juice (RGJ) and a novel, low furanocoumarin hybrid grapefruit juice (HGJ) on the metabolism of oral midazolam, used as a probe for in vivo CYP3A activity, compared with water as a control. The RGJ was 100% hand-squeezed Hudson grapefruit juice, and the HGJ contained low amounts of furanocoumarin constituents. The point estimates (90% confidence intervals) for the RGJ/water midazolam AUC geometric mean ratio was 122% (107 – 140). The point estimate for the HGJ/water midazolam AUC ratio was within the 80%-125% bioequivalence range, indicating an absence of interaction. This finding also prompted a systematic review of available evidence on the pharmacokinetic alteration of midazolam by grapefruit juice. While most studies demonstrated alteration in midazolam pharmacokinetics supporting inhibition of CYP3A activity as a likely mechanism, the cohorts included in these studies and the extent of the pharmacokinetic interaction varied widely. The current study indicated grapefruit juice-drug interaction varies substantially based on patient characteristics and/or grapefruit juice product-related factors, including the amount of furanocoumarin constituents present in the juice.

show abstract

The Effects of Milk Thistle (Silybum marianum) on Human Cytochrome P450 Activity

Cited by 50 publications

References 39 publications

Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review

Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review

An ex vivo approach to botanical–drug interactions: A proof of concept study

Effect of Low‐Furanocoumarin Hybrid Grapefruit Juice Consumption on Midazolam Pharmacokinetics

Contact Info

Product

Resources

About