Systematic review of pharmacokinetics and potential pharmacokinetic interactions of flavonolignans from silymarin

Abstract

Silymarin is an extract from the seeds (fruits) of Silybum marianum that contains flavonolignans and flavonoids. Although it is frequently used as a hepatoprotective agent, its application remains somewhat debatable, in particular, due to the low oral bioavailability of flavonolignans. Moreover, there are claims of its potential interactions with concomitantly used drugs. This review aims at a systematic summary and critical assessment of known information on the pharmacokinetics of particular silymarin flavonolignans. There are two known major reasons for poor systemic oral bioavailability of flavonolignans: (1) rapid conjugation in intestinal cells or the liver and (2) efflux of parent flavonolignans or formed conjugates back to the lumen of the gastrointestinal tract by intestinal cells and rapid excretion by the liver into the bile. The metabolism of phase I appears to play a minor role, in contrast to extensive conjugation and indeed the unconjugated flavonolignans reach low plasma levels after common doses. Only about 1%–5% of the administered dose is eliminated by the kidneys. Many in vitro studies tested the inhibitory potential of silymarin and its components toward different enzymes and transporters involved in the absorption, metabolism, and excretion of xenobiotics. In most cases, effective concentrations are too high to be relevant under real biological conditions. Most human studies showed no silymarin–drug interactions explainable by these suggested interferences. More interactions were found in animal studies, likely due to the much higher doses administered.

Irinotecan-Induced Steatohepatitis: Current Insights

“…Silymarin is a hepatoprotective agent, and it is derived from the seeds of Silybum marianum (43). As a natural flavonoid, silymarin has antioxidative effects and can decrease the oxidative stress in the liver (44).…”

Chirality Matters: Biological Activity of Optically Pure Silybin and Its Congeners

“…There are over 200 papers dealing with various pharmacological aspects of silymarin ADME (absorption, distribution, metabolism, and excretion), including that of silybin (for reviews, see [103][104][105]).…”

Silybin and its congeners: from traditional medicine to molecular effects

“…62 A linear relationship between oral silymarin dose and maximum silybin plasma concentration (C max ) was found in human volunteers, but not in animal models (rat, rabbit, and dog). 53 In human plasma, avonolignans and their sulfated metabolites are mainly bound to a specic site of serum albumin. 63,64 Flavonolignans are metabolized predominantly via phase II reactions, i.e., conjugation (methylation, 65 sulfation, 66 glucuronidation, 67 and glutathione conjugation 68 64), (Fig.…”

“…65,69 Phase I metabolism is negligible even in vitro. 53,66 Moreover, the reactions in both phases are stereoselective. 53,65,66 The conjugated metabolites can be effluxed directly from intestinal cells as well as excreted via bile; most conjugates formed in the liver are rapidly excreted into the bile.…”