Chinese Herb-Drug Interactions
Recently, we have had several practitioners inquire about the potential risks associated with treating their patients with Chinese herbs while taking a prescription drug or drugs for the ongoing pestilence of COVID-19. Are there interactions that may alter, enhance, or harm a patient’s response to simultaneous therapies involving a pharmaceutical and an herb formula? The short answer is that there certainly is, but by most research, the effect can also net positive therapeutic results. In the following discussion, we will examine some of the mechanisms of action involved in the pharmacodynamics and pharmacokinetics of drug therapy and the ways in which herbs and drugs interact.
To illustrate the ever-present circumstance of the interrelation of these different approaches, an investigation of the anti-COVID drug, Paxlovid (Nirmatrelvir + Ritonavir) and the first line Chinese herbal formula, Qingfei Paidu decoction (QFPD) will be discussed. Of course, there are other interventions that are possible in the standard of care in each tradition, but these will serve our purpose. For a detailed examination of most of the first-line therapies for SARS-COVID-2, drug and herbal, see the research article from Ying et al. in the Resources section at the end of the article.
A Deeper Dive into Pharmacology
The study of medicines includes several closely related topics under the umbrella of pharmacology including Pharmacotherapeutics, Toxicology, Pharmacognosy, Pharmacodynamics, and Pharmacokinetics with the complexities involved in last two accounting for nearly all drug interactions. For most Traditional Chinese Medicine (TCM) students, when they have a course in pharmacology at school, scant attention is paid to the other topics of the discipline, and what they receive is an introduction and survey course in pharmacotherapeutics, usually designated by common drug categories. Unfortunately, this does not provide new practitioners with a thorough understanding of the mechanisms involved in possible drug interactions when wanting to prescribe Chinese herbs and faced with patients with complex medical histories already on regimens of pharmaceutical drugs.
Pharmacotherapeutics describes the clinical applications useful for diagnosis, prevention, and treatment of disease.
Toxicology encompasses contraindications, typical adverse events, and drug interactions. Toxicology also includes the study of poisons and their actions, detections, treatments, physiological conditions, and the signs and symptoms exhibited when drugs are taken in overdose or toxic amounts.
Pharmacognosy is the study of drugs, chemicals, and biochemicals obtained from medicinal plants, animals, fungi, and other natural sources. It focuses on the physical, chemical, biochemical, and biological properties of drugs, drug substances of natural origin, as well as the search for new drugs from natural sources. The study of pharmacognosy is particularly relevant to Chinese herbs.
Pharmacodynamics describes what a drug does to the body, including biochemical and physiological effects, the characteristics of each class of drug, and the drug’s mechanism of action. It is important to understand that with many drugs the mechanism of action is unknown, and this certainly applies to Chinese herb formulas, at least from a biomedicine perspective. In many cases, a drug is designed to interfere or modulate specific biochemical pathways of a cell, tissue, organ, system, or pathogen, often by affecting the function or structure of proteinaceous enzymes that catalyze vital cellular activity.
There are over 5000 biochemical reactions, that are ubiquitous across species, that are controlled by enzymes. To prevent certain undesired symptoms or disease outcomes from occurring, drugs are often designed to target the enzymes and pathways in pathogenic tissues and/or microbes while creating the least amount of harm to the individual being treated. The function of the enzymes falls into three classes, each of which may be the target for drug intervention. An enzyme may function as a substrate, meaning that part of its globulin surface acts as a location for a biochemical reaction. Some drugs or chemicals induce the expression of an enzyme, while others are used to inhibit such expression. Many of the harmful herb-drug interactions occur when the mechanism of action by either is blocked or compromised by the presence of the other.
Finally, and importantly relevant to a discussion of herb-drug interactions, as well as drug-drug, drug-food, and herb-food interactions, is pharmacokinetics.
Pharmacokinetics emphasizes the fluctuation in bioavailability and defines what the body does to the drug. Investigation includes optimal routes of administration, rate of absorption, distribution, metabolism, elimination, and excretion.
Optimal administration, absorption, and distribution factors are determined to get medicines into the blood circulation so that their effects can be delivered to organs, tissues, and cells and/or attack pathogenic microbes. The goal is to administer the correct dosage of a medicine such that the plasma level of the drug is maintained in a certain range, known as the therapeutic window. Too low a level and the effect may be insufficient; too high a level and toxicity may occur. The dosing regimen maintains the ideal range of plasma concentration, and the administration route is based mainly on how to place the drug into the circulatory system so that its structure and efficacy remain intact. It should be noted that Chinese herbs are primarily administered orally, either by pill/tablet/capsule or in a liquid form such as a decoction or tincture, while many pharmaceutical drugs are often administered intramuscularly or intravenously to avoid the difficulties encountered in the digestive system. One advantage of the oral administration of traditional Chinese herbals medicines is that many of them have a modulating effect on the microbiota of the intestines, which has been demonstrated to play a prominent role in the robustness of the immune system.
How Elimination and Excretion Affect Interactions
Although the complexities of the kinetics and dynamics of drug actions are myriad, many of the difficulties pursuant to interactions occur because the methods of elimination and excretion are irreversible, fixed, and time-bound. To examine this, let us look at some other concepts within pharmacokinetics.
The liver is the organ system that is primarily responsible for regulating the removal of administered medicines, while the kidney is principally tasked with excretion accounting for 90% of the removal. Non-nutritive chemicals are targeted for metabolism and elimination by the actions of the liver since they are considered foreign and potentially toxic. The liver is ideally situated to do its chemical magic because it receives all incoming blood from the GI tract, where all substances are absorbed, via the mesenteric veins, besides being an in-line component of the circulatory system.
The gall bladder, in conjunction with the large intestine, is involved in nearly 8% of excretion. Drugs excreted through bile are large, complex, and usually have both polar and lipophilic groups. This method of elimination is assisted when taken with sufficient dietary fiber and removed in the stool, otherwise, the chemicals may be reabsorbed. The other organs that are involved in elimination are the lungs through the exhalation, the skin’s perspiration (e.g. ethanol and anesthesia drugs), and to a much lower extent the saliva, tears, and importantly, breast milk, even though it is not an excretory organ, since most drugs (and herbal medicines) transfer into breast milk.
The biochemicals in drugs are either hydrophilic or lipophilic. Drugs that are weak acids or bases, meaning that they are part of a compound that, when dissolved in water, creates a + or – charge, are identified as hydrophilic (“water-loving”). They dissolve easily in water and are easily eliminated by the body but not necessarily easily distributed in the body because they cannot independently penetrate the lipid layer of cells. Most medicinal chemicals are lipophilic, i.e. “lipid loving”. They are organic chemicals that are uncharged and very easily absorbed by the body because they can cross the lipid layer of cells. However, they must be altered before they can be excreted by the kidneys.
The liver facilitates excretion by the kidneys by making a drug (or herbal ingredient) more water-soluble. The liver uses Phase I and Phase II detoxification systems to accomplish this goal. These systems use proteinaceous enzymes encoded in the DNA of liver cells to accomplish this biochemistry.
Phase I Metabolism changes the structure of drugs, so they are in a more hydrophilic form via oxidation, reduction, and hydrolysis. Oxidation is carried out by a superfamily of enzymes called cytochrome P450. These enzymes oxidize the lipophilic drugs into slightly basic compounds with a negative charge. Genes encoding P450 enzymes, and the enzymes themselves, are designated with the root symbol CYP for the superfamily, followed by a number indicating the gene family. There are over 300,000 CYP enzymes that can be marshalled by the liver on demand to accomplish its goals. These globulin proteins oxidize steroids, fatty acids, and importantly for this discussion, xenobiotics i.e., foreign chemicals that are not naturally produced or expected to be present within an organism, including pharmaceutical and herbal medicines.
P450 reduction is less common and describes an enzymatic process in which hydrogen molecules are added to lipophilic drugs to create a positively charged compound. Hydrolysis is employed to break down lipophilic drugs by the addition of a water molecule, which creates two charged compounds (one positive and one negative). Both negative and positively charged compounds are easily removed by the kidneys.
Phase II Metabolism uses conjugation to add a molecule that can carry an ionic charge to the lipophilic drug, making it possible for the kidneys to remove the newly charged compounded chemical from the body. Sulfate, glutathione, acetic acid, or glucuronate are typically used for this purpose.
Metabolism and elimination begin immediately after absorption in the small intestine since the circulatory system passes through the liver before continuing its journey. Up to 30% of a xenobiotic is removed from the blood in initial encounter with the liver. This is known as the first pass effect. This is an important consideration in determining the initial dose of any medicine.
Another important concept in metabolism is the half-life. Half-life is determined by the amount of time it takes the body to eliminate 50% of any xenobiotic. Certain types of drugs are eliminated by enzymes that are limited in availability and are thus removed by a constant amount (grams) per unit of time. The best example of this is ethanol, which has a half-life of 3-6 hours, depending on the initial dose, your body weight (affects distribution), and how much water is in your body. A single standard alcoholic drink contains 14g of ethanol. By 3-6 hours, only 7 g will remain, and after 12 hours, <1g will remain. In actual practice, for the average person, it could take as much as 24 hours to completely remove alcohol from the body, even though its major CNS (Central Nervous System) effect may have worn off long before that.
Most medicines, in contrast, are eliminated by a constant percentage (%) per unit of time. 50% is removed in the first half-life and 50% of the remainder in the next, and this halving continues until the chemical is removed. Generally, five half-lives are necessary to remove ~98% of anything. Pharmaceutical companies conduct extensive research in determining the half-life of a drug since the half-life is an important determinant in the dosing regimen required to keep the plasma level of a drug within the therapeutic window. It is used to predict how long it takes a drug to reach steady state, which is usually 4-5 half-lives, and to assess how long it takes to clear a drug from the body, which can be important when selecting treatment options in adverse event or overdose situations.
One can roughly determine the half-life of any drug by examining the frequency of the next dose. One dose per day means the half-life is ~24 hours; three times per day means the half-life is about eight hours. Unfortunately, given the sheer number of constituent ingredients in an herbal formula, it is not possible to determine the half-life of an herbal formula and the dosing of many formulas are defaulted to 3x/day (every eight hours). Clinical judgment and regular follow-up with the patient are required for a practitioner to determine the correct dose for best results.
What are Drug Interactions?
Drug interactions are changes to pharmacology (all aspects) that can occur between drugs, herbs, and foods. All biochemicals that are orally ingested are subject to and have their own effect on digestion, adsorption, metabolism, and elimination. Some of these effects are intentional or therapeutic. There are numerous opportunities for these molecules to react together creating unique or altered chemicals, change physical conditions such as pH and solubility, compete for or obstruct chemical receptors, CYP enzymes, protein carriers, and challenge kidney clearance. These interactions can interfere with the results of laboratory tests, ECGs and other medical procedures, shorten or prolong therapy time, create adverse or toxic events, or produce physical or chemical incompatibilities. The more medicines, from any source, a patient receives, the greater the chances are that an, perhaps unforeseen, interaction will occur.
Potential drug interactions include effects that are additive, synergistic, potentiating, antagonistic, or toxic. See Side Bars for drug interaction shorthand formulas and acronyms found in the text.
An additive effect occurs when two drugs with similar therapeutic actions are administered to a patient. The effect is equivalent to nearly the sum of the effects of either drug administered alone, even in higher doses. E.g., Prescribing two analgesics/ painkillers (such as acetaminophen and hydrocodone) has several potential advantages. First, a lower dose of each drug can be combined to reach the same relief. Also, there is a decreased probability of adverse reactions, reduced tolerance, and greater pain control than from one drug given alone (probably because of different mechanisms of action). When administering Chinese herb formulas to a patient already taking pharmaceuticals or other functional medicines, the hope is that the combination of herbs and other medicines falls into this category.
Similarly, a potentiation effect occurs when two drugs that are intended to produce the same therapeutic effect are given together, and one drug potentiates or enhances the effect of the other drug or, alternatively, creates a synergistic effect that does not occur when the medicines are given separately.
An antagonistic drug interaction occurs when the combined response of two drugs is less than the response produced by either drug alone. In some cases, the actions of a drug can be completely negated or blocked due to the interaction.
Incompatibility is characterized by the interaction of two (or more) medicines that results in an increase in the number or severity of adverse symptoms. An increase in adverse and toxic effects occurs principally when a drug's metabolism and/or excretion are inhibited by another drug, resulting in increased plasma levels and reduced drug clearance. When a drug is not removed in its expected time, an overdose situation can ensue, and the resultant toxicity can cause serious symptoms and even become life-threatening. Alternatively, the combination of two or more medicines could create new chemicals which are toxic.
First, the good news. Herb‒drug interactions (HDIs) that may occur during Chinese herbal therapy combined with antiviral drug treatment of patients with COVID-19 are not clinically harmful, and they do not require any special medical care or monitoring.
Although many of the phytochemicals present in Chinese herbs use, compete for, induce, inhibit, or activate many CYP genes and their encoded enzymes, in most cases, there are no known deleterious effects on pharmaceutical drug therapy. In fact, the combination of drugs and Chinese herbs is primarily described as additive, potentiating, or synergistic. The National Health Commission of China announced that early TCM herbal intervention with COVID-19 patients, in combination with antiviral drugs, resulted in effective relief of symptoms, quicker viral shedding time, and shorter hospital stays, thereby reducing not only morbidity but also mortality. In addition, research has shown that TCM formulae can inhibit the replication and transcription of SARS-CoV-2 by targeting a specific viral protease (3CLpro aka Mpro) and RNA-dependent polymerase (RdRp) and can attenuate cytokine storm and immune deficiency caused by the SARS-CoV-2. To illustrate a possible clinical example, let us examine the co-prescription of Paxlovid™ and Qingfei Paidu Decoction (QFPD).
Paxlovid™ is a therapeutic combination consisting of two compounds: Nirmatrelvir and Ritonavir. The combination illustrates a purposeful employment of drug-drug interactions. Paxlovid™ reduces the risk of hospitalization or mortality by 89% in non-hospitalized adult patients with COVID-19. Nirmatrelvir, which is designed to prevent viral replication, is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro, sometimes designated 3CLpro). Peptidomimetics are peptides, which are chains of amino acids smaller than a protein, which are introduced to mimic the mode of action of native peptides, in this case, a viral peptide that naturally regulates viral replication. Co-administration with a low dose of Ritonavir, which is a potent inhibitor of CYP3A4 and several other metabolizing enzymes, that is used to slow down the hepatic metabolism of Nirmatrelvir, leading to longer periods of higher concentrations of Nirmatrelvir to combat the virus. Both Nirmatrelvir and Ritonavir are excreted primarily in feces and to a much lesser extent in urine than many other drugs.
Qingfei Paidu Decoction (QFPD) is composed of 20 herbs and one mineral (see Side Bar), and it has been determined to contain a total of 195 chemical components, including metabolites. QFPD is listed as the first-line prescription of TCM clinical treatment in the latest Protocol on Diagnosis and Treatment of COVID-19 issued by China’s National Health Commission (the complete report can be downloaded here.) Previous studies have shown that QFPD acts on several targets associated with its anti-inflammation, immuno-modulation, and anti-viral effects against COVID-19. ACE2 (the major cell entry receptor for the virus), SARS-CoV-2 spike protein, and SARS-CoV-2 3CLpro, which are closely relevant to the infectivity and pathogenicity of COVID-19, are also identified as the potential targets of QFPD.
In addition, numerous studies have demonstrated that TCM formulae are important in the positive modulation of gut microbiota and restoring bacterial diversity, which can be critical in the treatment of COVID-induced pneumonia. Gut microbiota alterations have been reported in hospitalized COVID-19 patients and are related to poor prognosis through complex interactions with SARS-CoV-2 and host immunity after severe COVID-19. More importantly, the composition of the microbial community may not be fully restored in COVID-19 patients even after a 3-month recovery. It was also reported that ACE2 expression may be regulated by microbiota via their metabolites.
Eschewing the familiar TCM functions, let us examine some of the highlights of the pharmacodynamic and pharmacokinetic features of each herb in QFPD. The effects on CYP enzymes are omitted because every herb contains many phytochemicals, all of which utilize various CYP pathways. Within a particular formula, the phytochemicals are generally present only in low quantities and the potential for conflict is likewise small, except as noted.
Ephedrae Herba (Ma huang) is the dried herbaceous stem of Ephedra sinica. Arguably the emperor herb in this formula, Ma huang could disrupt the interaction between ACE2 and SARS-CoV-2 spike protein receptor-binding domain, thereby abolishing the infectivity of SARS-CoV-2. To date, more than 150 chemical components of Ephedrae Herba have been identified with phenylalkylamine alkaloids including ephedrine, pseudoephedrine, methylephedrine, norephedrine, and norpseudoephedrine considered to be characteristic active compounds. Ephedrine, pseudoephedrine, and methylephedrine are permeability glycoprotein (P-gp) substrates. (P-gp is a key component of viral cell membranes.) Remember that a substrate is the location of action of certain enzymes and this action of Ma huang damages the viral cell membrane. As typical of many herbs, Ephedrae Herba has an increased effect on certain metabolizing enzymes, while inhibiting or inducing others.
Glycyrrhizae Radix et Rhizoma Praeparata Cum Melle (Zhi gan cao) is the dried root and rhizome of Glycyrrhiza uralensis that has been processed with honey.
Studies have revealed Zhi gan cao could inhibit ACE2, thereby inhibiting viral infectivity and showing affinity to RdRp of SARS-CoV-2, suggesting its potential efficacy against COVID-19. Numerous bioactive constituents have been found in Glycyrrhiza including the familiar glycyrrhizin and glycyrrhetinic acid. Glycyrrhetinic acid has been suggested as a substrate for P-gp. Glycyrrhizin is poorly absorbed by the gastrointestinal tract but extensively metabolized by the intestinal microflora into glycyrrhetinic acid. Zhi gan cao has numerous effects on many CYP (and other enzyme systems). Based on previous reports, Zhi gan cao modulates gut microbiota, thereby enhancing the immune defensive function of the human body. Treatment using Glycyrrhizae Radix et Rhizoma together with Astragali Radix significantly attenuated the decreased diversity, reduced richness, and abnormal composition of intestinal microbiota, which may explain its traditional function of “harmonizing”.
Armeniacae Semen Amarum (Ku xing ren) is the dried ripe seed of Prunus armeniaca. Ku xing ren has been shown to possess an antiviral effect because of its strong affinity to 3CLpro and ACE2, thereby preventing viral transcription and dissemination. Its pharmacokinetic characterization is reflected by the presence of the phytochemical amygdalin. Amygdalin might be a substrate for P-gp. Amygdalin has evident inhibitory effects on the activity of certain CYP enzymes. It is well known that amygdalin is considered toxic due to its metabolite of cyanide in vivo. However, certain members of the intestinal microbiota that are involved in bidirectional regulation of toxicity and detoxification of amygdalin along with the low bioavailability of amygdalin means that the toxicity of Ku xing ren is low.
Gypsum Fibrosum (Sheng shi gao) is a common mineral/herb known as “stone paste” and is composed of primarily hydrated calcium sulfate. Its cold nature has been used since antiquity for reducing fever, treating Fire syndromes, and alleviating thirst. Gypsum Fibrosum might exhibit an inhibitory effect on the activity of certain CYP enzymes, which may lead to some drug interactions in vivo.
Cinnamomi Ramulus (Gui zhi) is the dried young branch of Cinnamomum cassia that has been found to inhibit the activity of Zika virus by inhibiting RdRp activity. More than 121 chemical compounds have been isolated from Cinnamomi Ramulus, with Cinnamic acid being an important bioactive compound found in the herb. The extract of Gui zhi and lactic acid bacteria have been suggested in the upregulation of the alpha diversity of gut microbiota in mice. Alpha diversity refers to both the number and distribution of organisms. Low alpha diversity is characteristic of a dysbiotic microbiome.
Alismatis Rhizoma (Ze xie) is the dried rhizome of Alisma orientale. Ze xie has been reported to inhibit the infection and replication of various enteroviruses and rhinoviruses. A wide range of chemical compounds have been isolated from Ze xie. Among these compounds, alisol acetates are important bioactive triterpenoids that play various pharmacological effects. Alisol B 23-acetate can increase the expression of pregnane X receptor (PXR), which is a steroid and xenobiotic sensing nuclear receptor whose primary function is the detoxification and clearance of these substances, effectively treating hypercholesterolemia and dyslipidemia. In addition, alisol B 23-acetate could alleviate liver damage by activating farnesoid X receptor (FXR), whose function is the upregulation of the enzyme that controls the formation of bile salts from cholesterol. Both activities, along with its actions on CD-4 cells and certain interleukins can improve the immune inflammatory response. Importantly in the treatment of COVID-19, alisol B 23-acetate and alisol F 24-acetate could downregulate viral permeability glycoprotein (P-gp). Ze xie can also improve the changes in gut microbial structure caused by diabetes, (a disease considered high risk for COVID complications) and affect microbiota-associated with lipid metabolism.
Polyporus (Zhu ling), a widely used medicinal fungi, has been used as food, antidote, and diuretic for centuries in Chinese medicine. Zhu ling was reported to exert an antiviral effect by inhibiting SARS-CoV-2. Polyporus polysaccharides include ergone and ergosterol. Both chemicals are primarily excreted in feces via bile. Ergone has potent cytotoxic effects on certain cancer cells inducing apoptosis. Ergosterol is a potent anti-fungal drug and is a biological precursor of Vitamin D.
Atractylodes Macrocephala Rhizoma (Bai zhu) is the dried rhizome of Atractylodes macrocephala. Bai zhu might be a potential herb against SARS-CoV-2 through binding to ACE2. Studies have shown that Bai zhu could strongly activate human PXR. It has been reported that Atractylenolide I and Atractylenolide III could inhibit glucuronosyltransferase (UGT) activity, an enzyme used in the conjugation and subsequent elimination of potentially toxic xenobiotics and certain endogenous compounds, especially toxic estrogen metabolites. This could be responsible for increased serum levels of some drugs although high doses may be required to see a significant effect. It has also been suggested that atractylenolide III could also significantly modulate downregulated gut microbiota.
Poria (Fu ling), the dried sclerotia of Poria cocos that has been used as a TCM medicinal herb for over 2000 years. A study revealed that Poria exerted an inhibitory effect on the aforementioned SARS-CoV-2 main protease (Mpro). The main active components of Poria are triterpenes and polysaccharides. It has been reported that Poria polysaccharides inhibit, induce, or reduce the expression of various CYP genes. Pachymic acid found in Fu ling activated pregnane X receptor (PXR). Poria could also induce transcriptional expression of several cytochrome genes that remove toxic substances in liver cells. Pachymic acid and dehydrotumulosic acid isolated from Poria could inhibit P-gp function. Poria polysaccharides could regulate the gut microbiota to alleviate certain intestinal injuries affecting the diversity of gut microbiota.
Bupleuri Radix (Chai hu) is a traditional herbal medicine derived from the dried roots of Bupleurum chinense. Triterpenoid saponins, flavonoids, and essential oils are considered the main bioactive compounds. Saikosaponins are potential candidates of Chai hu for COVID-19 treatment since several of the fractions of the chemical have inhibitory actions on several CYP enzymes involved in the removal of xenobiotics. Regarding COVID drugs, such as Paxlovid, this may increase the half-life of the drug allowing it to be present at higher doses and for a greater length of time in the circulatory system. Saikosaponins exhibit evident anti-inflammatory, antitumor, antiviral, anti-allergic, immunoregulation, and neuroregulation activities. Saikosaponin a, saikosaponin c, and saikosaponin d also inhibited P-gp. Additionally, saikosaponin d could regulate the gut microbiota, including the upregulation of healthy gut bacteria.
Scutellariae Radix (Huang qin) is the dried root of Scutellaria baicalensis. Over 40 compounds have been isolated and identified from Huang qin including baicalin, baicalein, wogonin, chrysin and oroxylin A, which have been shown to inhibit H1N1 (Swine flu) activity. It has been suggested that baicalin and baicalein could inhibit RdRp of SARS-CoV-2 and P-gp activity and expression. It has been reported that polysaccharides isolated from Huang qin could upregulate gut microbiota.
Pinelliae Rhizoma Praeparatum (Zhi ban xia) is the dried tuber of Pinellia ternate. Alkaloids, essential oils, amino acids, organic acids, and proteins are the chemical components of Ban xia. β-Sitosterol, a bioactive compound could interact with Mpro of SARS-CoV-2. Pinelliae Rhizoma showed inhibitory effects on CYP3A activity, the most common enzyme in liver metabolism of many drugs and xenobiotics. This inhibition is similar to the furanocoumarin in grapefruit juice and the net effect may lead to increased plasma concentrations and lengthier half-lives of some drugs.
Zingiberis Rhizoma Recens (Sheng jiang) is fresh Ginger. More than 100 compounds have been identified from Ginger, and its bioactive components include essential oils, gingerols, among others, with gingerols being recognized as important active ingredients. 6-Gingerol is the principal ingredient of Ginger that exerts anti-inflammatory and antioxidant effects and 10-gingerol has an inhibitory effect on COVID-19. Previous studies have shown that Sheng jiang extract could inhibit or increase various CYP-mediated drug metabolic pathways. 6-Gingerol has been reported to inhibit P-gp activity and Ginger polysaccharides may modulate immune function by affecting the diversity of beneficial and harmful gut microbiota.
Asteris Radix et Rhizoma (Zi wan) is the dried root and rhizome of Aster tataricus. Shionone, astin D, and epifriedelinol are three characteristic compounds of Zi wan. Epifriedelanol could enhance cytotoxicity by down-regulating the mRNA and protein expression of P-gp and MRP- 2 (a multidrug resistant-associated protein).
Farfarae Flos (Kuan dong hua) is the dried flower bud of Tussilago farfara. Previous studies showed that the compounds in Kuan dong hua can bind to SARS-CoV-2 vital protease 3CLpro and ACE2, thereby exerting a therapeutic effect against COVID-19. Organic acids are considered active compounds of Farfarae Flos that demonstrate mild or weak inhibition of certain CYP enzymes and glucuronosyltransferase (needed for conjugation of some drugs in the liver). One of these acids, chlorogenic acid, regulates intestinal homeostasis and reduces the body's inflammatory response.
Belamcandae Rhizoma (She gan) is the dried rhizome of Belamcanda chinensis. Flavonoids are the main active components for She gan’s pharmacological effects, including tectorigenin, irigenin, and irisflorentin. These flavonoids are suggested as being responsible for the inhibition of several viral CYP genes and enzymes. Some of these flavonoids may be involved in potentiation of drug interactions.
Asari Radix et Rhizoma (Xi xin) is the dried root and rhizome of several Asarum species. Sesamin and asarinin, two active compounds isolated from Xi xin, showed inhibitory potential against SARS-CoV-2 3CLpro in computer modeling. Asarinin is the index component (marker chemical) for the identification and content determination. Sesamin could strongly downregulate the mRNA and protein levels of certain viral CYP genes, and it could significantly increase the mRNA expression of several MDRs. In vitro, sesamin promotes the proliferation and adhesion of intestinal probiotics leading to the beneficial modulating of gut microbiota.
Dioscoreae Rhizoma (Shan yao) is the dried rhizome of Dioscorea oppositae. Polysaccharides and starch are considered the main bioactive macromolecules in Shan yao. Dioscoreae Rhizoma extract could regulate intestinal flora and its starch could inhibit the pathogenic bacteria of E. coli and Helicobacter hepaticus.
Aurantii Fructus Immaturus (Zhi shi) is the dried young fruit of Citrus aurantium. Flavanone glycosides were determined as the active compounds in Aurantii Fructus Immaturus. Naringin, naringenin, hesperidin, and hesperetin are the substrates of P-gp and the ethanol extract of Zhi zi could upregulate the protein levels of P-gp. Eight flavonoid aglycones of Zhi zi show anti-inflammatory activity, especially in the human gut microbiota.
Citri Reticulatae Pericarpium (Chen pi) is the dried pericarp of the ripe fruit of Citrus reticulata. Hesperidin, nobiletin, and tangeretin are the quality control index components of Chen pi. Besides its multiple effects on several enzyme systems, Chen pi has a regulatory effect on intestinal microorganisms, especially short chain fatty acids-producing and anti-inflammatory bacteria.
Pogostemonis Herba (Guang huo xiang) is the dried aerial part of Pogostemon cablin. A study revealed that compounds in Guang huo xiang can bind to the active site of SARS-CoV-2 3CLpro. Patchouli alcohol and pogostone are known as the active compounds in Guang huo xiang which affect P-gp and MRP. Pogostemonis could modulate intestinal microbiota affecting the main producing bacteria for short chain fatty acids-producing bacteria and can bind to the active site of SARS-CoV-2 3CLpro.
Final Thoughts
Although the interaction of this pairing of a pharmaceutical drug and a Chinese herbal formula appears positive, this may not always be the case in your clinical practice. Let me offer a couple of suggestions. First, every healthcare practitioner must obtain a complete list of the drugs and supplements that a patient is receiving. Each medicinal substance must be researched extensively, focusing on its intent, mechanism of action, known adverse effects, and known interactions. I recommend accessing the information available at PDR.net or drugs.com. (See drug info resources at the bottom of this document.) One important reason for this investigation is that your patient’s chief or significant complaint, for which they are seeking treatment, may actually be an adverse effect of their drug therapy. Progress may be difficult if they are regularly dosing themselves with the very cause of their symptoms. In addition, if you are choosing to add Chinese herbs to the mix, you will be aware of potential or new adverse effects that may be caused by a drug-herb interaction. I always suggest checking in with a patient 5-7 days after initiating herbal therapy to see if the patient is taking the herbs and if they are experiencing any untoward effects. Besides the listed adverse effects related to the drug, be aware of reports of nausea, vomiting, diarrhea, or itching which may be harbingers of an interaction or of an allergy or sensitivity that may be induced by the herbs or by the interactions.
Second, research potential interactions on PubMed or Google Scholar. While a lot of information is obtained during the research and development of pharmaceutical drugs, including potential interactions with other pharmaceuticals and certain foods (which can be found in the PDR or drugs.com), the data on interaction between drugs and herbs is limited, at least in the US. This is changing and there is a significant amount of research (largely from outside the US) that can be accessed on PubMed (you will have to create an account) or Google Scholar. Search for the herb or formula by Latin binomial or pinyin name and the generic or brand name of a drug. Perhaps, not surprisingly, hospitals, universities, and researchers in Asia (and elsewhere) are investigating the concomitant use of drugs and herbal medicine. Most of this information is accessible if you are willing to engage in the arcane language of medical research.
About the Author
Skye Sturgeon, DAOM is the Quality Assurance Manager and Special Consultant for Mayway, USA. Skye was the former Chair of Acupuncture & East Asian Medicine and core faculty member at Bastyr University, core faculty member and Faculty Council Chair at the American College of Traditional Chinese Medicine, and President and Senior Professor of the Acupuncture & Integrative Medicine College, Berkeley. Before making Chinese medicine his career choice, Skye held various positions in the Natural Foods Industry for 12 years and prior to that was a clinical biochemist and toxicologist.
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Drug Info Resources
Online Physicians’ Desk Reference
www.pdr.net
The PDR contains the Food and Drug Administration’s approved uses and labeling for pharmaceutical drugs, prescription information provided by manufacturers for grandfathered drugs and other drugs marketed without FDA approval. The PDR content includes a description, common brand names, and the class of a drug. It also contains indications, effects, dosages, routes of administration, methods, mechanism of action, frequency of dosage, and any relevant warnings, interactions, hazards, contraindications, side effects, and precautions. The site also provides a link to download a mobile version.
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