Женьшень и рак Обзоры Клинические исследования Ginseng & cancer Review


POTENTIAL GINSENG-DRUG INTERACTIONS



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  • COMMENTARY

POTENTIAL GINSENG-DRUG INTERACTIONS


An herbal medicine such as ginseng has many different constituents, each of which exerts a distinct pharmacological activity. With its complex pharmacodynamics and pharmacokinetics, ginseng may place patients who take it concurrently with prescription medications at potential risk for ginseng-drug interactions.

Despite the public enthusiasm for herbal medicines, scientific knowledge of herbal-drug interaction is incomplete and often confusing for health care professionals and patients. Recommendations to avoid herbal-drug interaction are often based on in vitro observations, animal studies, and case reports. However, data from clinical studies, especially controlled clinical trials, are often unavailable.

When Yu et al. compared the effect of American ginseng and Asian ginseng extracts on gene expression of the hepatic P450 enzyme in adult rats and primary cultures or rat hepatocytes, there was no evidence of the induction of CYP2B1, CYP3A23, or CYP1A2 cultures of rat [47]. In another study ginseng had no effect on a number of CYP isoforms, including CYP3A4, CYP1A2, CYP2E1 and CYP2D6 [48, 49]. However, in elderly humans, CYP2D was slightly inhibited [49].

Liu et al. evaluated the ginseng influence on hepatic P450 activities using both naturally occurring ginsenosides and their degradation products in gut lumen with human liver microsomes and cDNA-expressed CYP3A4. The naturally occurring ginsenosides exhibited no or weak inhibition against human CYP3A4, CYP2D6, CYP2C9, CYP2A6, or CYP1A2 activities. Intestinal metabolites inhibited P450-mediated metabolism. Compound K, protopanaxadiol (PPD), and protopanaxatriol (PPT) inhibited CYP2C9 activity moderately; PPD and PPT also strongly inhibited CYP3A4 activity. These data suggest that after oral administration, naturally occurring ginsenosides may influence hepatic P450 activity in vivo via ginseng’s intestinal metabolites [50].

Andrade et al. evaluated the pharmacokinetic effects of American ginseng in healthy volunteers taking the HIV protease inhibitor indinavir. Indinavir decreased insulin sensitivity, but this decrease was unaltered by co-administration of American ginseng. American ginseng did not significantly affect indinavir pharmacokinetics [51].

Herb-drug interaction is particularly important when a drug has a narrow therapeutic index and keeping the drug effect in a target range is crucial. Herbs such as ginseng may interact with warfarin, an oral anticoagulant with a narrow therapeutic window [52, 53]. A widely cited case report showed a substantial decrease in the anticoagulant effect of warfarin after ginseng consumption in a patient whose warfarin therapy had been stable previously [52, 53].

In a randomized, double-blind, placebo-controlled trial to evaluate the potential interactions between American ginseng and warfarin, 20 health subjects participated in a 4-week study [54]. During weeks 1 and 4, subjects received warfarin for 3 days. Beginning in week 2, patients received either American ginseng or placebo. The international normalized ratio (INR) and plasma warfarin levels were measured. Peak INR decreased significantly after 2 weeks of ginseng administration compared with 2 weeks of placebo. There was also a statistically significant reduction in INR area under the curve (AUC), peak plasma warfarin level, and warfarin AUC in the ginseng group compared with the placebo group. Steroids can induce hepatic enzyme activities [55]. Ginsenosides may also enhance enzyme functions. Whether ginseng interferes with other hepatically metabolized drugs remains to be evaluated.

The reduction of warfarin’s anticoagulant effect by American ginseng was not supported in studies using another ginseng species. Neither Asian [56] nor Korean red ginseng [57] significantly interacted with warfarin. Because warfarin is often used following orthopedic or vascular procedures, the potential for drug interaction is more than theoretical in nature and deserves further evaluation.

The effect of ginseng on coagulation pathways has raised concerns. Ginsenosides inhibited platelet aggregation in vitro [58] and in rats they prolonged both thrombin time and activated partial thromboplastin time [59]. One study suggested that the antiplatelet activity of panaxynol, a constituent of ginseng, might be irreversible in humans [60]. Recently, Lee et al. evaluated ginsenosides Rg6, F4, Rk3, Rh4, Rs3, Rs4, and Rs5 isolated from processed ginseng for their effects on platelet aggregation. The degree of inhibitory activity on platelet aggregation varied [61, 62]. Because platelet inhibition by ginseng may be irreversible, it is prudent for surgical patients to discontinue ginseng use at least one week before surgery [63].

COMMENTARY


Pharmacokinetics deals with the process by which a drug is absorbed, the magnitudes of the desired response as a function of the drug concentration at the site of action, the drug metabolism, and its elimination from the body. Drug plasma concentrations over time are often obtained with the assumption that they are the concentrations at the site of action. Like other herbal medicines, ginseng harbors many different components, such as ginsenosides, polysaccharides, and peptides. Several dozen ginsenosides have been identified in the ginseng plant. Although nearly all of them belong to a family of steroids, some of their pharmacokinetic parameters vary by species. To connect the pharmacokinetics of one ginsenoside to its pharmacodynamic activity is of limited usefulness because when ginseng root is ingested, one ginsenoside may also alter the pharmacokinetics of another ginsenoside. Further complicating the study results of ginseng is that the potency of the plant products is often measured by total ginsenoside content, which varies from lot to lot. Cultivation conditions such as soil, temperature, moisture, length of cultivation, and harvest season can change total ginsenoside content, or ginsenoside percentages, thus altering ginseng kinetics [64, 65].

Conventionally, the metabolism of a new compound in humans is studied in vivo using radiotracer techniques for absorption and disposition. Ideally, the metabolism of a new compound is evaluated in vitro before clinical studies. In some studies, hepatic P450 has catalyzed ginsenoside metabolism in hepatocytes. Yet when ginseng root is studied in vivo, pharmacokinetic interaction of ginsenosides may exist.

Many prescription drugs have one or more metabolites that may have their own biological effects. Taken orally, the bioavailability of ginseng is low, and many of the parent ginsenosides are converted to metabolites by gut microbiota. Some of these metabolites, such as Compound K, possess significantly stronger cancer chemoprevention activity than the parent compounds. Pharmacologically, the parent compound and its metabolites may act by similar mechanisms, different mechanisms, or even by antagonism. Pharmacokinetically, the active metabolites of ginseng differ in distribution and clearance from that of the parent compound. Further studies are needed before the pharmacokinetic information of ginseng’s metabolites can be used to predict therapeutic outcome in humans.



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