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Li, J.;  Wang, S.;  Tian, F.;  Zhang, S.;  Jin, H. Pharmacokinetic Mechanisms of Transporter-Mediated Herb-Drug Interactions . Encyclopedia. Available online: https://encyclopedia.pub/entry/27228 (accessed on 22 June 2025).
Li J,  Wang S,  Tian F,  Zhang S,  Jin H. Pharmacokinetic Mechanisms of Transporter-Mediated Herb-Drug Interactions . Encyclopedia. Available at: https://encyclopedia.pub/entry/27228. Accessed June 22, 2025.
Li, Jie, Shuting Wang, Fengjie Tian, Shuang-Qing Zhang, Hongtao Jin. "Pharmacokinetic Mechanisms of Transporter-Mediated Herb-Drug Interactions " Encyclopedia, https://encyclopedia.pub/entry/27228 (accessed June 22, 2025).
Li, J.,  Wang, S.,  Tian, F.,  Zhang, S., & Jin, H. (2022, September 16). Pharmacokinetic Mechanisms of Transporter-Mediated Herb-Drug Interactions . In Encyclopedia. https://encyclopedia.pub/entry/27228
Li, Jie, et al. "Pharmacokinetic Mechanisms of Transporter-Mediated Herb-Drug Interactions ." Encyclopedia. Web. 16 September, 2022.
Pharmacokinetic Mechanisms of Transporter-Mediated Herb-Drug Interactions 
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This entry is adapted from the peer-reviewed paper 10.3390/ph15091126

As the use of herbs has become more popular worldwide, there are increasing reports of herb-drug interactions (HDIs) following the combination of herbs and drugs. The active components of herbs are complex and have a variety of pharmacological activities, which inevitably affect changes in the pharmacokinetics of chemical drugs in vivo.

drug transporters herbs herb–drug interactions

1. HDIs That Improve Therapeutic Efficacy and/or Reduce Toxicity

Many herbs in combination therapies with chemical drugs exert synergistic and/or additive effects, and in some cases, alleviate side effects or toxicity of the concomitantly used drug. Many studies have shown that this may be related to the regulation of transporters by herbs and their derivatives, which can affect absorption, distribution, and excretion of substrates by inducing or inhibiting the activity of drug transporters, in order to achieve the effect of enhancing efficacy or reducing toxicity [1]. Here are some reported herbs that can increase drug efficacy or reduce drug toxicity mediated by transporters (Table 1).

1.1. Securidaca inappendiculata Hassk.

Securidaca inappendiculata Hassk. is a traditional herbal medicine used to treat fractures, inflammation, and rheumatoid arthritis. Flavone derivatives are the main bioactive components promoting the anti-rheumatic properties of this plant [2][3].
Clinically, MTX is often used to treat rheumatoid arthritis, but in long-term treatment, it was found that because renal excretion constitutes the major elimination route of MTX, MTX treatment can cause nephrotoxicity in vivo, even at a very low dose [4]. Therefore, some researchers have wondered whether the combination of Securidaca inappendiculata Hassk. and MTX can be used to enhance efficacy and reduce the toxicity of MTX. Recent studies have found that a xanthone-rich fraction (XRF) in Securidaca inappendiculata Hassk. weakened MTX-induced proximal tubular edema. The experimental results show that XRF pre-treatment augmented MTX secretion into urine. XRF treatment significantly restored the suppressed OAT3 expression induced by MTX, as revealed by immunoblotting assay. OAT3 was extensively expressed in proximal renal tubules under normal conditions. MTX treatment diminished it greatly. The combined use of XRF totally reverts this trend. XRF promoted the excretion of MTX into urine by increasing the expression of OAT3. As a result, XRF attenuated MTX-induced edema of the proximal tubule. In vitro experiments showed that XRF restored the expression of OAT3 and enhanced the uptake capacity of MTX by HEK 293T cells, which indicated that XRF effectively protected MTX-induced renal secretion impairment by restoring the expression of OAT3. However, it is worth noting that the bioavailability of MTX was reduced to a large extent. Thus, it is worth paying attention to how to balance safety and efficacy in combined treatments [5].

1.2. Morinda officinalis F.C. How.

Morinda officinalis F.C. How. (Rubiaceae) (MO), also known as “Bajitian” in Chinese, is one of the most famous herbs in China, South Korea, and Japan. In traditional Chinese medicine (TCM), MO is often used to treat various diseases, including male impotence [6], female infertility, fatigue, chronic rheumatism, and depression. Modern pharmacological experiments have shown that MO has a wide range of pharmacological activities, including antioxidant, analgesic, anti-inflammatory, anti-osteoporosis, antidepressant, and fertility-promoting activities [7][8]. MO has also been shown to help improve memory and treat Alzheimer’s disease [9][10][11]. Bajijiasu (BJJS) is one of the main bioactive compounds isolated from MO, which has a variety of pharmacological activities and therapeutic effects. Doxorubicin is a cancer chemotherapeutic drug and a substrate of P-gp. BJJS activated Nrf2, induced the expression of P-gp, enhanced the efflux activity of P-gp and reduced the toxicity of doxorubicin to cells [12]. Although the combination of MO and doxorubicin can reduce toxicity, it is still necessary to pay attention to detrimental HDIs due to the regulation of MO on P-gp [12].

1.3. Other Herbal Active Ingredients

Flavonoids

Flavonoids have been proven to have anti-hypertension, diabetes, cardiovascular disease and other activities, and have been listed as the main components of drugs and health products, including troxerutin tablets and ginkgo biloba, which are also widely distributed in herbal foods, increasing the possibility of using them together with other drugs. It is necessary to consider the interaction between flavonoids and other drugs [13].

Rutin

Rutin is a flavonol that is abundant in plants such as passionflower, buckwheat, tea, and apple. It is an important nutritional component in food. Chemically, it is a glycoside, which is composed of the flavonoid glycoside quercetin and rutin disaccharide. It has many pharmacological activities, including antioxidant, cell protection, vascular protection, anticancer, neuroprotective, and cardioprotective activities [14]. Diclofenac is a widely used non-steroidal anti-inflammatory drug for the treatment of various inflammatory diseases. Although diclofenac is well absorbed orally, it can produce gastrointestinal diseases and cardiovascular complications. Studies have found that in rats, the therapeutic effect (anti-nociceptive and anti-inflammatory activity) of diclofenac is enhanced in the presence of rutin. Diclofenac is a substrate of BCRP, and rutin can inhibit the expression of BCRP. The research mechanism shows that rutin can enhance the intestinal permeability of diclofenac which may be related to the regulation of rutin on BCRP. Therefore, rutin has been found to be a promising drug candidate that can improve the efficacy of diclofenac through the expected HDIs. In the future, suitable diclofenac and rutin pharmaceutical compositions can be established with improved efficacy and better tolerance [15].

Quercetin

Quercetin is one of the most studied flavonoid compounds and has antioxidant and anti-aging effects. Most of these flavonoid compounds are in the form of glycosides, such as rutin, quercetin, hyperin, etc., and are widely present in berberine, hypericum, and other common plants [16]. Quercetin can inhibit the expression of P-gp [17][18].
Irinotecan is a semi-synthetic derivative of camptothecin, which has a growing clinical impact due to its effectiveness in colon, lung, pancreatic, cervical, and ovarian malignancies, with increased survival benefits for patients. However, it has the side effect of diarrhea which is associated with excessive bile excretion of its metabolite 7-ethyl-10-hydroxy camptothecin (SN-38). Pharmacokinetic studies showed that the absolute bioavailability of irinotecan in female Wistar rats pretreated with quercetin increased by 1.3 times compared with the control group. Mechanism studies showed that quercetin can increase the plasma concentration and reduce the bile levels of irinotecan and SN-38 by inhibiting intestinal P-gp activity, and improved the diarrhea caused by irinotecan [19]. These results suggest that the regulation of P-gp by quercetin in combination with anticancer drugs is likely to improve adverse reactions in patients, which is worthy of further clinical trials.

Apigenin

Apigenin is a flavonoid compound, which is widely distributed in natural plants and is present in vegetables and fruits, especially in celery. Compared with other flavonoids, apigenin has advantages due to its low inherent toxicity. Apigenin inhibits several drug transporters, such as OATP1B1, OATP1B3, and OAT1 [20]. Adefovir is an antiviral drug that can cause nephrotoxicity during treatment. Some studies have used apigenin and adefovir at the same time and found that apigenin effectively inhibited the activity of OAT1 in a dose-dependent manner. At the dose of 50 μM, apigenin significantly reduced the cytotoxicity of adefovir in MDCK-OAT1 cells and significantly increased cell viability from 50.6% to 112.62%. This showed that apigenin regulates OAT1 and can cause HDIs when used in combination with adefovir. When apigenin is used in combination with the substrate of OAT1, apigenin can be used as a renal protector [21].

Resveratrol

Resveratrol is a polyphenol found naturally in red grapes, mulberries, and peanuts. In addition to its well-known effects as a powerful antioxidant, resveratrol possesses extensive beneficial activities. These include anti-inflammatory, antiplatelet aggregation, anti-fibrotic, anti-allergic, and anti-aging actions. Resveratrol has been shown to exhibit profound multiorgan protective effects, including on the cardiovascular system, liver, and neurons, although many of the resveratrol-induced in vivo positive effects are only achieved at relatively high doses and long treatment periods, probably due to its extensive metabolism [22].
Resveratrol can up-regulate the expression of BCRP in the kidney. BCRP is mainly distributed in the apical membrane of tubules in the kidney and participates in the urinary clearance of organic anionic drugs. When resveratrol is combined with MTX, the ATPase activity of human BCRP increases, which activates the protective mechanism of the kidney, accelerates the clearance of MTX in urine and reduces nephrotoxicity [22]. Other studies have shown that resveratrol reduces the testicular toxicity of MTX by up-regulating the expression of MRP3 [23]. Different than the detoxification effect of resveratrol on MTX, some studies have investigated the mechanism of resveratrol in enhancing the toxicity of cisplatin. The experiments showed that resveratrol could reduce the absorption of glutamine by inhibiting the expression of the glutamine membrane transporter (ASCT2) and then enhancing the sensitivity of cells to cisplatin chemotherapy [24]. It can be seen that the regulation of transporters by resveratrol combined with drugs will protect the organs and promote the cytotoxicity of cancer cells, which is of significant benefit in clinical treatment.

Berberine

Berberine is an isoquinoline alkaloid present in many plants, including Coptis chinensis. It is an important component with pharmacological activity in Chinese herbal medicine. Berberine has a wide range of effects and can be used in the treatment of diabetes, inflammation, bacterial and viral infections, and cardiovascular diseases [25]. Metformin, a biguanide derivative, is extensively eliminated in the kidney as the parent drug (79–86% of an intravenous dose) via tubular secretion mediated by OCTs. As both metformin and berberine can be used for the treatment of diabetes, some studies have examined the pharmacokinetic interaction between metformin and berberine in vivo after oral administration. Uptake transporters such as OCT1 located in the liver and OCT2 located in the kidney transport berberine from the blood into liver or kidney tubular epithelial cells and play an important role in the tissue distribution and elimination of berberine. The study found that metformin increased the Cmax and AUC0–4h of berberine by 33.1% and 57.7%. The cell inhibition test revealed that metformin (≥ 1 and ≥ 0.3 mM) decreased the berberine concentration in MDCK-rOCT1 and MDCK-rOCT2 cells. So the co-administration of metformin probably inhibited the uptake of berberine by the liver and kidney and then increased the plasma concentration. Therefore, metformin combined with berberine might be beneficial in the treatment of diabetes [26][27].

2. HDIs That Produce Adverse Reactions

Although researchers can enhance the efficacy of chemical drugs or reduce their toxicity by regulating the expression of transporters using herbs (Table 1), researchers cannot ignore the possible additional adverse reactions caused by HDIs due to the regulation of herbs on transporters which will have a negative impact on clinical treatment. Several cases of HDIs due to transporters and the corresponding mechanisms were identified in the literature in order to confirm the mechanism and possible risk of HDIs caused by transporters and are shown in Table 2.
Table 1. Effects of herbal extracts or components on transporters and the beneficial impact of HDIs.
Herbs Chemical Composition/Drugs Methods Transporter Effect Affected Drugs/Herbs Reactions References
Securidaca inappendiculate Hassk. xanthone-rich fraction in vivo, rats;
in vitro, HEK 293T cells		 OAT3 ↑ methotrexate Promote methotrexate excretion and reduce proximal tubular edema [5]
Morinda officinalis F.C. How. bajijiasu in vivo, mice;
in vitro, HepG2 cells		 P-gp ↑ doxorubicin Promote doxorubicin efflux and reduce cytotoxicity [12]
Herbal active
ingredients		 flavonoids rutin in vivo, rats; BCRP ↓ diclofenac Increase the intestinal permeability of diclofenac and improve the curative effect [14][15]
quercetin in vivo, rats;
in vitro, Caco-2 cells (HTB-37)		 P-gp ↓ irinotecan Increase the blood concentration of irinotecan, reduce the level of irinotecan in bile and improve the diarrhea caused by irinotecan [19]
apigenin in vivo, rats;
in vitro, MDCK-OAT1 cells		 OAT1↓ adefovir Reduced cytotoxicity [21]
resveratrol in vivo, rats BCRP ↑ methotrexate Promotes the clearance of methotrexate in urine and reduces nephrotoxicity [22]
in vivo, rats;
in vitro, PC3 cells		 MRP3↑ Promote MTX efflux
in vitro, C3A, SMCC7721 and LO2 cells ASCT2 ↓ cisplatin Glutamine metabolism is inhibited, which promotes the sensitivity of human liver cancer cells to cisplatin chemotherapy [24]
  metformin in vivo, rats;
in vitro, HEK293-OCT1 and -OCT2 cells		 OCT1 ↓ berberine Increase the plasma concentration of berberine. [27]
MATE1 ↓
↑, inducing; ↓, inhibitory.

2.1. Red Ginseng

The active components of ginseng mainly include ginsenosides, polysaccharides, alkaloids, peptides, and phenolic compounds, which have anti-inflammatory, antidiabetes, anticancer, anticardiovascular, and cerebrovascular disease activity, and plays an important role in traditional Chinese herbal medicine [28]. Red ginseng is the root and rhizome of raw ginseng after steaming and drying under high temperatures and high pressure. Although it is different from the processing technology for ginseng, it is also defined as “ginseng” and has more abundant pharmacological activities [29].
Red ginseng contains a variety of bioactive components, including flavonoids, phenolic acids, and ginsenosides. It is reported that red ginseng extract (RGE) has an anti-diabetes role by preventing mitochondrial damage and inhibiting intracellular inflammation [30]. As red ginseng can reduce oxidative stress damage induced by hyperglycemia, some diabetic patients take red ginseng and its preparations as adjuvant treatment when taking prescription drugs for diabetes, which may produce adverse HDIs. It is reported that repeated RGE administration for one week can increase the expression of OCT1 mRNA in rat intestine and promote the absorption of metformin [31]. This is related to the expression site of uptake transporter OCT1 in the intestine. OCT1 is located in the apical membrane of intestinal cells. RGE increases the intestinal uptake and transport of metformin by increasing the level of OCT1 protein, thus increasing the plasma concentration of metformin. Metformin can cause diarrhea, and an increase in metformin blood concentration may cause more serious side effects; therefore, cautious is necessary when combined with red ginseng.
Experiments have been carried out to study the effect of RGE on efflux transporters. One week after intragastric administration of RGE (1.5 g/kg/d), the mRNA and protein levels of MRP2, BSEP, and P-gp in rat liver were monitored. It was found that repeated RGE administration reduced the expression of MRP2. The pharmacokinetics of MTX, the substrate of MRP2 probe, was further studied in rats. It was shown that bile excretion of MTX was reduced and the area under the plasma drug time curve was increased by 1.5 times in the RGE repeated administration group compared with the control group [32]. In the liver, MRP2 is located in the apical membrane of hepatocytes and is responsible for pumping drugs in the liver into bile for clearance. Long-term administration of red ginseng can reduce the expression of MRP2 and the clearance of MTX, resulting in increased exposure to drugs in the body. MTX, an immunosuppressant and antitumor drug commonly used in the clinic, has a narrow treatment window. The change in blood drug concentration caused by the use of herbal medicine requires further attention [33]. Long-term multi-dose administration of RGE can reduce the hepatobiliary excretion of MRP2-specific substrates, thus inducing unnecessary HDIs, which requires therapeutic drug monitoring and determination of the safety of clinical combinations.

2.2. Radix astragali

Radix astragali is a common Chinese herbal medicine. Its effective components include saponins, isoflavones, polysaccharides, and various trace elements. It has the functions of protecting the liver, diuresis, analgesia, sedation, and enhancing body immunity [34]. As Radix astragali can activate human immune function, it is mostly used as a dietary supplement in daily life or as a clinical adjuvant.
Experiments have shown that Radix astragali and its three main active components, including astragaloside IV, calyx anthocyanin, and formononetin, can induce the expression of P-gp and BCRP and increase the efflux function mediated by P-gp and BCRP by activating the Nrf2 mediated signal pathway [35]. A study on the effect of astragaloside IV on the pharmacokinetics of omeprazole in vivo was carried out in male rats. It was found that following pretreatment with astragaloside IV (100 mg/kg/d for 7 days), the Cmax and AUC0–t of omeprazole (2 mg/kg) in rats were 74% and 61% of those in the control group, respectively. A transport study in the Caco-2 cell line found that after pretreatment with astragaloside IV, the efflux ratio of omeprazole in the trans Caco-2 cell transport model increased from 1.73 to 2.67. This suggests that astragaloside IV may reduce the absorption of omeprazole in the intestine by inducing the efflux activity of P-gp, in order to reduce the bioavailability of omeprazole in vivo [36]. In addition, experiments have proven that when puerarin is used in combination with astragaloside IV, it also reduces the exposure in vivo due to the induction of P-gp by astragaloside IV [37]. These results suggest that potential HDIs may occur when Radix astragali or its active components are used in combination with other drugs, which are P-gp and BCRP substrates. Whether these potential HDIs will reduce the efficacy or increase the induced toxicity needs to be further verified in the clinic and by research.

2.3. St John’s Wort

St. John’s wort (SJW), also known as Hypericum perforatum L., is a perennial herb of Hypericum. and has the effect of sedation and hypnosis. Its antidepressant effect has been confirmed by many studies. It is the preferred herbal medicine for the treatment of depression and anxiety in European countries and America [38].
Studies have shown that SJW can induce P-gp activity and produce clinical HDIs when used together with P-gp substrates [39]. SJW increased P-gp expression and enhanced drug excretion in peripheral blood lymphocytes from healthy volunteers [40]. The pharmacokinetic effects of SJW on digoxin were evaluated by chemiluminescence immunoassay. Eighteen young volunteers (9 women and 9 men) received SJW extract (300 mg, 3 times/d) and other control drugs for 14 days, followed by digoxin (0.25 mg), and blood samples were tested continuously within 24 h. The results showed that compared with the control group, SJW administration led to a significant decrease in the Cmax and AUC of digoxin, which could lead to more clinically significant P-gp-mediated HDIs [40]. In another single-blind, placebo-controlled parallel study, 25 healthy volunteers (12 women, 13 men) received a continuous load of oral digoxin (0.25 mg, twice a day) for two days, followed by 0.25 mg of digoxin daily up to day 15. Volunteers took SJW extract and placebo from day 6 to day 15, and blood samples were collected on day 5 (before combined administration), day 6, and day 15 for pharmacokinetic analysis. The experiment showed that the AUC and Cmax of digoxin in the SJW extract group decreased by 33% and 26%, respectively, compared with the placebo group after day 15 of oral administration, and this absorption inhibition effect was continuously enhanced compared with day 6 [41][42]. These findings showed that the pharmacokinetic effect of SJW extract on digoxin is time-dependent, and this phenomenon is related to the induction of active expression of P-gp.
Cyclosporine (CSP), an important immunosuppressant with a narrow therapeutic window, is widely prescribed to prevent allograft rejection in transplant patients and to treat rheumatoid arthritis and psoriasis. The use of CsA in transplantation medicine has been shown to cause a number of toxic cellular side effects, including nephrotoxicity, hepatotoxicity, neurotoxicity, and myocardial toxicity [43]. In some clinical cases, it was also found that taking SJW during CSP treatment in organ transplant recipients induced a reduction in the concentration of CSP in plasma to the sub-therapeutic level, resulting in acute rejection [44][45][46]. SJW can not only promote the expression of P-gp, but also induce the activity of CYP3A4 [47]. CSP is the common substrate of CYP3A4 and P-gp. SJW-mediated HDI may be the result of the interaction between transporters and metabolic enzymes. SJW reduces the absorption of CSP in the intestine by increasing the expression of intestinal P-gp, which may indirectly prolong the enzymatic reaction of CYP3A4 to CSP and enhance the first pass effect of the drug. Due to the large mucosal surface area and rich blood flow of the small intestine, its unique structural characteristics determine that the small intestine is the main place for food digestion and absorption, while the expression of P-gp is abundant in the small intestine, and the retention time of oral drugs in the intestine is longer, which increases the opportunity for this interaction.

2.4. Polygonum cuspidatum

Polygonum cuspidatum (PC), a medicinal plant of the Polygonaceae family of eudicots, has the effects of clearing away heat and detoxification, promoting dampness, and resolving phlegm. It is an important component of traditional Chinese herbal medicine. Modern pharmacological research has shown that PC has anti-inflammatory and antioxidant effects and can be used to treat cancer and other inflammatory diseases [48][49].
Carbamazepine (CBZ) is the substrate of P-gp and MRP2. These two efflux transporters are distributed in the basolateral membrane of brain endothelial cells and play a protective role in the BBB. They are considered to be one of the main reasons for CBZ resistance and recurrent seizures. It has been reported that PC can significantly increase the systemic exposure and brain drug concentration of CBZ by inhibiting the activities of MRP2 and CYP3A [50]. In patients treated with CBZ, attention should be paid to avoiding toxicity when combined with PC. On the contrary, for patients with resistance to CBZ, combined treatment with PC may help to reverse resistance. Careful monitoring of the combination of PC and key drugs (substrates of CYP3A4 and/or MRP 2) is very important in the clinic.

2.5. Rheum palmatum

Rheum palmatum (RP) is a commonly used herb in clinical Chinese medicine which has the functions of antibacterial and anti-inflammatory, cholagogic and liver protection, heat-clearing, and detoxification. The major constituents of rhubarb are a variety of phenolic compounds, such as anthraquinone derivatives, dianthrones, stilbenes, polyphenols, flavonoids, and chromones. Recent pharmacokinetic studies of RP have revealed that the anthraquinones were predominantly present as glucuronides and sulfates in the blood, and they are also putative substrates of MRPs and OATs [51][52].
Phenytoin (PHT), a widely used antiepileptic with a narrow therapeutic window, follows nonlinear pharmacokinetics, and thus therapeutic drug monitoring is usually recommended during its use. The adverse reactions of PHT include drowsiness, dysarthria, tremor, and cognitive difficulties. PHT has been reported to be a substrate of P-gp and MRP2, whose expression determines the PHT level in the brain. Some studies have observed the acute and chronic effects of RP on the pharmacokinetics of phenytoin sodium in rats. The results showed that when combined with RP, it could significantly reduce the Cmax and AUC of phenytoin sodium in rats. Cell experiments showed that RP could significantly induce the activity of P-gp and mediate the efflux of phenytoin sodium, but inhibit the activity of MRP2. In an experiment, it was found that the oral bioavailability of phenytoin sodium decreased after combined administration in rats. It can be inferred that this was achieved by enhanced expression of P-gp activity by RP [53]. Studies have found that RP can activate the functions of P-GP and CYP 3A, and significantly reduce the Cmax and AUC0-t of CSP in rats. RP–CSP interaction might pose a nonnegligible hidden risk of allograft rejection for transplant patients. RP might lead to potential herb-drug interactions with substrate drugs of P-gp and/or CYP 3A4, which might result in therapeutic failure [43].

2.6. Dioscorea bulbifera L.

Dioscorea bulbifera L. (DB) is a clinical Chinese herbal medicine with a wide range of pharmacological activities. The extract from DB rhizomes contains a variety of components, including diterpene lactones, steroidal saponins, flavonoids, alkaloids, and micronutrients. It has an antitumor effect and can inhibit cervical cancer and liver cancer [54].
Pirarubicin (THP) is an anthracycline drug that interferes with DNA synthesis in tumor cells. It is widely used in the treatment of several tumors. However, the clinical application of THP is severely limited due to its severe cardiotoxicity, which is irreversible, and the drug can accumulate. Some studies have evaluated the effects of the combination of DB and THP on liver and heart injury in mice, the accumulation of THP, and the localization and expression of P-gp and MRP2 to study the mechanism of HDIs between DB and THP. The results showed that when DB extract was combined with THP, the expression of P-gp and MRP2 was down-regulated, the excretion of THP was reduced, and then accumulated in vivo, aggravating cardiotoxicity. Therefore, it is necessary to monitor cardiotoxicity in the clinic when DB extract and THP are administered together [55].

2.7. Other Herbal Active Ingredients

Flavonoids

Paracetamol (acetaminophen) is a para-aminophenol derivative and possesses analgesic and antipyretic activities similar to aspirin. Studies have evaluated the effect of the flavonoid quercetin on the pharmacokinetics of paracetamol in rats. Paracetamol (100 mg/kg) combined with quercetin (5, 10, 20 mg/kg) was administered by gavage once a day for 21 days, and blood samples were taken for analysis. The results showed that quercetin could increase the plasma exposure of paracetamol in a dose-dependent manner. After combined administration of quercetin (20 mg/kg), the AUC of paracetamol increased from 26.44 ± 6.79 to 64.47 ± 6.80 mg h/mL, the half-life in vivo was prolonged, and the clearance rate was reduced. In the non-everted rat gut sac method, the absorption of paracetamol was increased in the presence of quercetin. As mentioned above, quercetin can inhibit the expression of P-gp. Paracetamol is metabolized by glucuronidation (40–67%) and sulfation (20–46%) into inactive and harmless metabolites. Quercetin has been reported to be a potent inhibitor of the production of both sulfate and glucuronide conjugates of paracetamol in cultured cells. These findings suggest that quercetin might inhibit P-gp and the metabolism of paracetamol, thereby increasing systemic exposure to paracetamol [56]. This suggests that quercetin can inhibit P-gp-mediated paracetamol transport and increase systemic exposure to drugs. The excessive accumulation of drugs in the body may induce and aggravate the hepatotoxicity of paracetamol. Thus, careful dosing is needed when paracetamol is co-administered with quercetin.

Sinapic acid

Sinapic acid (SA) is a phenolic acid, which is abundant in human foods, such as berries, citrus fruits, nuts, coffee and tea, and whole grains, as well as traditional herbs rich in erucic acid. It is used as a sedative, anticonvulsant, antidepressant, and antiepileptic drug (mustard, cabbage, black mustard, pyrethrum, kidney-shaped sweet potato, mistletoe, corn) [12][57][58][59].
The antiepileptic drug CBZ is effective in the treatment of seizures, convulsions, trigeminal neuralgia, and manic depression, but long-term use of CBZ can lead to liver injury. In patients with epilepsy who need long-term treatment, clinicians should provide liver protective dietary supplements. However, due to the narrow treatment window of CBZ, this may lead to potential HDIs. Studies have shown that CBZ is an effective inducer of various drug metabolic enzymes, such as CYP450 3a and 2b in the liver, and the metabolism of CBZ is related to transporters P-gp and MRP-2 [60]. A study using male Wistar rats was carried out to investigate the pharmacokinetic effect of SA on CBZ. It was found that the blood concentration of CBZ after SA pretreatment was higher than that without pretreatment. SA significantly inhibited the metabolism of CBZ in the liver mediated by CYP3A2 and CYP2C11, significantly inhibited the efflux of CBZ by intestinal P-gp, increased intestinal absorption, and improved the absorption rate of CBZ. This greatly increased the probability of liver injury. However, further studies are needed to determine the clinical relevance of these observations. Therefore, when taking CBZ, foods containing SA or traditional herbs should be used with caution [61].
Table 2. Effects of herbal extracts or components on transporters and HDIs that produce adverse reactions.
Herbs Chemical Composition Methods Transporter Effect Affected Drugs Reactions References
Red ginseng red ginseng extract (RGE) in vivo, rats;
in vitro, HEK293 cells		 OCT1 ↑ metformin Increase the blood concentration of metformin, easy to cause diarrhea [31]
in vivo, rats; MRP2 ↓ methotrexate Bile excretion is reduced, methotrexate clearance is reduced, and burst leakage in the body is increased, prone to side effects [32]
Radix astragali astragaloside IV in vivo, rats;
in vitro, Caco-2 cell line		 P-gp ↑ omeprazole Decrease the absorption of omeprazole [36]
St John’s wort - in vivo, human P-gp ↑ digoxin Reduce the absorption of digoxin in the intestine and reduce the bioavailability of drugs [41][42]
in vivo, human ciclosporin Reduce the absorption of ciclosporin in the intestine and enhance the first pass effect of drugs, produce acute rejection [44][45][46]
Polygonum cuspidatum - in vivo, rats
in vitro, LS 180 and MDCKII–MRP 2 cell lines		 MRP2↓ carbamazepine Increased systemic exposure to carbamazepine, causing carbamazepine resistance and recurrent seizures [50]
Rheum palmatum - in vivo, rats;
in vitro, LS 180 and MRP-2-overexpressing MDCK II
cell lines		 P-gp ↑ phenytoin Promote the efflux of phenytoin sodium, reduce the bioavailability and reduce the curative effect [53]
MRP2 ↓ drugs with MRP2 as substrate Increase the amount of drug leakage in the body and increase the toxicity [53]
  in vivo, rats P-gp ↑ cyclosporine Reduce the systemic exposure of CSP and increase the risk of allogeneic rejection [43]
Dioscorea bulbifera L. extract from Dioscorea bulbifera L. rhizomes in vivo, mice P-gp ↓
MRP2 ↓		 pirarubicin Reduce pirarubicin exclusion, pirarubicin accumulation in the body and aggravate cardiotoxicity [55]
herbal active ingredients quercetin in vivo, rats;
in vitro, Caco-2 cells		 P-gp ↓ paracetamol Increase blood drug concentration of paracetamol and aggravate liver toxicity [56]
Sinapic acid in vivo, rats P-gp ↓ carbamazepine Inhibit the excretion of drugs in the intestine and metabolism in the liver, increase the absorption of carbamazepine and enhance liver injury [53][60][61]
↑, inducing; ↓, inhibitory.

References

  1. Kato, S.; Ito, K.; Kato, Y.; Wakayama, T.; Kubo, Y.; Iseki, S.; Tsuji, A. Involvement of Multidrug Resistance-Associated Protein 1 in Intestinal Toxicity of Methotrexate. Pharm. Res. 2009, 26, 1467–1476.
  2. Zuo, J.; Xia, Y.; Li, X.; Chen, J.-W. Therapeutic effects of dichloromethane fraction of Securidaca inappendiculata on adjuvant-induced arthritis in rat. J. Ethnopharmacol. 2014, 153, 352–358.
  3. Olatunji, O.J.; Zuo, J.; Olatunde, O.O. Securidaca inappendiculata stem extract confers robust antioxidant and antidiabetic effects against high fructose/streptozotocin induced type 2 diabetes in rats. Exploration of bioactive compounds using UHPLC-ESI-QTOF-MS. Arch. Physiol. Biochem. 2021, 1–13.
  4. Bedoui, Y.; Guillot, X.; Sélambarom, J.; Guiraud, P.; Giry, C.; Jaffar-Bandjee, M.C.; Ralandison, S.; Gasque, P. Methotrexate an Old Drug with New Tricks. Int. J. Mol. Sci. 2019, 20, 5023.
  5. Wang, D.-D.; Li, Y.; Wu, Y.-J.; Wu, Y.L.; Han, J.; Olatunji, O.J.; Wang, L.; Zuo, J. Xanthones from Securidaca inappendiculata antagonized the antirheumatic effects of methotrexate in vivo by promoting its secretion into urine. Expert Opin. Drug Metab. Toxicol. 2021, 17, 241–250.
  6. Song, B.; Wang, F.; Wang, W. Effect of Aqueous Extract from Morinda officinalis F. C. How on Microwave-Induced Hypothalamic-Pituitary-Testis Axis Impairment in Male Sprague-Dawley Rats. Evid.-Based Complement. Altern. Med. 2015, 2015, 360730.
  7. Li, N.; Qin, L.-P.; Han, T.; Wu, Y.-B.; Zhang, Q.-Y.; Zhang, H. Inhibitory Effects of Morinda officinalis Extract on Bone Loss in Ovariectomized Rats. Molecules 2009, 14, 2049–2061.
  8. Liang, J.; Hao, H.; Lin, H.; Wang, P.; Wu, Y.; Jiang, X.; Fu, C.; Li, Q.; Ding, P.; Liu, H.; et al. The Extracts of Morinda officinalis and Its Hairy Roots Attenuate Dextran Sodium Sulfate-Induced Chronic Ulcerative Colitis in Mice by Regulating Inflammation and Lymphocyte Apoptosis. Front. Immunol. 2017, 8, 905.
  9. Deng, S.; Lu, H.; Chi, H.; Wang, Y.; Li, X.; Ye, H. Neuroprotective Effects of OMO within the Hippocampus and Cortex in a D-Galactose and Aβ25–35-Induced Rat Model of Alzheimer’s Disease. Evid.-Based Complement. Altern. Med. 2020, 2020, 1067541.
  10. Cai, H.; Wang, Y.; He, J.; Cai, T.; Wu, J.; Fang, J.; Zhang, R.; Guo, Z.; Guan, L.; Zhan, Q.; et al. Neuroprotective effects of bajijiasu against cognitive impairment induced by amyloid-β in APP/PS1 mice. Oncotarget 2017, 8, 92621–92634.
  11. Zhang, J.-H.; Xin, H.-L.; Xu, Y.-M.; Shen, Y.; He, Y.-Q.; Yeh, H.; Lin, B.; Song, H.-T.; Liu, J.; Yang, H.-Y.; et al. Morinda officinalis How—A comprehensive review of traditional uses, phytochemistry and pharmacology. J. Ethnopharmacol. 2018, 213, 230–255.
  12. Yang, X.; Hu, G.; Lv, L.; Liu, T.; Qi, L.; Huang, G.; You, D.; Zhao, J. Regulation of P-glycoprotein by Bajijiasu in vitro and in vivo by activating the Nrf2-mediated signalling pathway. Pharm. Biol. 2019, 57, 184–192.
  13. Yuan, H.; Wang, Y.; Chen, H.; Cai, X. Protective effect of flavonoids from Rosa roxburghii Tratt on myocardial cells via autophagy. Biotech 2020, 10, 58.
  14. Ganeshpurkar, A.; Saluja, A.K. The Pharmacological Potential of Rutin. Saudi Pharm. J. 2017, 25, 149–164.
  15. Dogra, A.; Gour, A.; Bhatt, S.; Sharma, P.; Sharma, A.; Kotwal, P.; Wazir, P.; Mishra, P.; Singh, G.; Nandi, U. Effect of rutin on pharmacokinetic modulation of diclofenac in rats. Xenobiotica 2020, 50, 1332–1340.
  16. Patel, R.V.; Mistry, B.M.; Shinde, S.K.; Syed, R.; Singh, V.; Shin, H.-S. Therapeutic potential of quercetin as a cardiovascular agent. Eur. J. Med. Chem. 2018, 155, 889–904.
  17. Bai, J.; Zhao, S.; Fan, X.; Chen, Y.; Zou, X.; Hu, M.; Wang, B.; Jin, J.; Wang, X.; Hu, J.; et al. Inhibitory effects of flavonoids on P-glycoprotein in vitro and in vivo: Food/herb-drug interactions and structure-activity relationships. Toxicol. Appl. Pharmacol. 2019, 369, 49–59.
  18. Wongrattanakamon, P.; Nimmanpipug, P.; Sirithunyalug, B.; Chansakaow, S.; Jiranusornkul, S. A significant mechanism of molecular recognition between bioflavonoids and P-glycoprotein leading to herb-drug interactions. Toxicol. Mech. Methods 2018, 28, 1–11.
  19. Bansal, T.; Awasthi, A.; Jaggi, M.; Khar, R.K.; Talegaonkar, S. Pre-clinical evidence for altered absorption and biliary excretion of irinotecan (CPT-11) in combination with quercetin: Possible contribution of P-glycoprotein. Life Sci. 2008, 83, 250–259.
  20. Fan, X.; Bai, J.; Hu, M.; Xu, Y.; Zhao, S.; Sun, Y.; Wang, B.; Hu, J.; Li, Y. Drug interaction study of flavonoids toward OATP1B1 and their 3D structure activity relationship analysis for predicting hepatoprotective effects. Toxicology 2020, 437, 152445.
  21. Wu, T.; Li, H.; Chen, J.; Cao, Y.; Fu, W.; Zhou, P.; Pang, J. Apigenin, a novel candidate involving herb-drug interaction (HDI), interacts with organic anion transporter 1 (OAT1). Pharmacol. Rep. 2017, 69, 1254–1262.
  22. El-Sheikh, A.A.; Morsy, M.A.; Al-Taher, A.Y. Protective mechanisms of resveratrol against methotrexate-induced renal damage may involve BCRP/ABCG2. Fundam. Clin. Pharmacol. 2016, 30, 406–418.
  23. El-Sheikh, A.A.; Morsy, M.A.; Al-Taher, A.Y. Multi-drug resistance protein (Mrp) 3 may be involved in resveratrol protection against methotrexate-induced testicular damage. Life Sci. 2014, 119, 40–46.
  24. Liu, Z.; Peng, Q.; Li, Y.; Gao, Y. Resveratrol enhances cisplatin-induced apoptosis in human hepatoma cells via glutamine metabolism inhibition. BMB Rep. 2018, 51, 474–479.
  25. Imenshahidi, M.; Hosseinzadeh, H. Berberis Vulgaris and Berberine: An Update Review. Phytotherapy Res. 2016, 30, 1745–1764.
  26. Shi, R.; Xu, Z.; Xu, X.; Jin, J.; Zhao, Y.; Wang, T.; Li, Y.; Ma, Y. Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine. Eur. J. Pharm. Sci. 2019, 127, 282–290.
  27. Kwon, M.; Choi, Y.A.; Choi, M.-K.; Song, I.-S. Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin. Arch. Pharmacal Res. 2015, 38, 849–856.
  28. Irfan, M.; Kwak, Y.-S.; Han, C.-K.; Hyun, S.H.; Rhee, M.H. Adaptogenic effects of Panax ginseng on modulation of cardiovascular functions. J. Ginseng Res. 2020, 44, 538–543.
  29. Kawase, A.; Yamada, A.; Gamou, Y.; Tahara, C.; Takeshita, F.; Murata, K.; Matsuda, H.; Samukawa, K.; Iwaki, M. Effects of ginsenosides on the expression of cytochrome P450s and transporters involved in cholesterol metabolism. J. Nat. Med. 2014, 68, 395–401.
  30. Park, J.-K.; Shim, J.; Cho, A.-R.; Cho, M.-R.; Lee, Y.-J. Korean Red Ginseng Protects Against Mitochondrial Damage and Intracellular Inflammation in an Animal Model of Type 2 Diabetes Mellitus. J. Med. Food 2018, 21, 544–550.
  31. Jin, S.; Lee, S.; Jeon, J.-H.; Kim, H.; Choi, M.-K.; Song, I.-S. Enhanced Intestinal Permeability and Plasma Concentration of Metformin in Rats by the Repeated Administration of Red Ginseng Extract. Pharmaceutics 2019, 11, 189.
  32. Lee, S.; Kwon, M.; Choi, M.-K.; Song, I.-S. Effects of Red Ginseng Extract on the Pharmacokinetics and Elimination of Methotrexate via Mrp2 Regulation. Molecules 2018, 23, 2948.
  33. Lin, S.-P.; Yu, C.-P.; Hou, Y.-C.; Huang, C.-Y.; Ho, L.-C.; Chan, S.-L. Transporter-mediated interaction of indican and methotrexate in rats. J. Food Drug Anal. 2018, 26, S133–S140.
  34. Ma, X.Q.; Shi, Q.; Duan, J.A.; Dong, T.T.X.; Tsim, K.W.K. Chemical Analysis of Radix Astragali (Huangqi) in China: A Comparison with Its Adulterants and Seasonal Variations. J. Agric. Food Chem. 2002, 50, 4861–4866.
  35. Lou, Y.; Guo, Z.; Zhu, Y.; Zhang, G.; Wang, Y.; Qi, X.; Lu, L.; Liu, Z.; Wu, J. Astragali radix and its main bioactive compounds activate the Nrf2-mediated signaling pathway to induce P-glycoprotein and breast cancer resistance protein. J. Ethnopharmacol. 2019, 228, 82–91.
  36. Liu, W.; Liu, G.; Liu, J. Effects of astragaloside IV on the pharmacokinetics of omeprazole in rats. Pharm. Biol. 2019, 57, 449–452.
  37. Liu, L.; Li, P.; Qiao, L.; Li, X. Effects of astragaloside IV on the pharmacokinetics of puerarin in rats. Xenobiotica 2019, 49, 1173–1177.
  38. Barnes, J.; Anderson, L.A.; Phillipson, J.D. St John’s wort (Hypericum perforatum L.): A review of its chemistry, pharmacology and clinical properties. J. Pharm. Pharmacol. 2001, 53, 583–600.
  39. Wang, Z.; Hamman, M.A.; Huang, S.-M.; Lesko, L.J.; Hall, S.D. Effect of St John’s wort on the pharmacokinetics of fexofenadine. Clin. Pharmacol. Ther. 2002, 71, 414–420.
  40. Hennessy, M.; Kelleher, D.; Spiers, J.P.; Barry, M.; Kavanagh, P.; Back, D.; Mulcahy, F.; Feely, J. St John’s Wort increases expression of P-glycoprotein: Implications for drug interactions. Br. J. Clin. Pharmacol. 2002, 53, 75–82.
  41. Gurley, B.J.; Swain, A.; Williams, D.K.; Barone, G.; Battu, S.K. Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: Comparative effects of St. John’s wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics. Mol. Nutr. Food Res. 2008, 52, 772–779.
  42. Johne, A.; Brockmöller, J.; Bauer, S.; Maurer, A.; Langheinrich, M.; Roots, I. Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum). Clin. Pharmacol. Ther. 1999, 66, 338–345.
  43. Yu, C.-P.; Lin, H.-J.; Lin, S.-P.; Shia, C.-S.; Chang, P.-H.; Hou, Y.-C.; Hsieh, Y.-W. Rhubarb decreased the systemic exposure of cyclosporine, a probe substrate of P-glycoprotein and CYP 3A. Xenobiotica 2016, 46, 677–682.
  44. Gary, W.B.; Bill, J.G.; Beverley, L.K.; Meredith, L.L.; Sameh, R.A. Drug interaction between St. John’s Wort and cyclosporine. Ann. Pharmacother. 2000, 34, 1013–1016.
  45. Ruschitzka, F.; Meier, P.J.; Turina, M.; Lüscher, T.F.; Noll, G. Acute heart transplant rejection due to Saint John’s wort. Lancet 2000, 355, 548–549.
  46. Moschella, C.; Jaber, B.L. Interaction between cyclosporine and Hypericum perforatum (St. John’s wort) after organ transplantation. Am. J. Kidney Dis. 2001, 38, 1105–1107.
  47. Sprouse, A.A.; van Breemen, R.B. Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements. Drug Metab. Dispos. 2016, 44, 162–171.
  48. Zhang, Y.; Zheng, L.; Zheng, Y.; Zhou, C.; Huang, P.; Xiao, X.; Zhao, Y.; Hao, X.; Hu, Z.; Chen, Q.; et al. Assembly and Annotation of a Draft Genome of the Medicinal Plant Polygonum cuspidatum. Front. Plant Sci. 2019, 10, 1274.
  49. Pan, B.; Shi, X.; Ding, T.; Liu, L. Unraveling the action mechanism of polygonum cuspidatum by a network pharmacology approach. Am. J. Transl. Res. 2019, 11, 6790–6811.
  50. Chi, Y.-C.; Lin, S.-P.; Hou, Y.-C. A new herb-drug interaction of Polygonum cuspidatum, a resveratrol-rich nutraceutical, with carbamazepine in rats. Toxicol. Appl. Pharmacol. 2012, 263, 315–322.
  51. Wang, Z.-W.; Wang, J.-S.; Yang, M.-H.; Luo, J.-G.; Kong, L.-Y. Developmental Changes in the Composition of Five Anthraquinones from Rheum palmatum as Quantified by (1) H-NMR. Phytochem. Anal. 2013, 24, 329–335.
  52. Wang, L.; Pan, X.; Sweet, D.H. The anthraquinone drug rhein potently interferes with organic anion transporter-mediated renal elimination. Biochem. Pharmacol. 2013, 86, 991–996.
  53. Chi, Y.-C.; Juang, S.-H.; Chui, W.K.; Hou, Y.-C.; Chao, P.-D.L. Acute and Chronic Administrations ofRheum palmatumReduced the Bioavailability of Phenytoin in Rats: A New Herb-Drug Interaction. Evid.-Based Complement. Altern. Med. 2012, 2012, 701205.
  54. Lim, J.W.; Chee, S.X.; Wong, W.J.; He, Q.L.; Lau, T.C. Traditional Chinese medicine: Herb-drug interactions with aspirin. Singap. Med. J. 2018, 59, 230–239.
  55. Sun, L.-R.; Guo, Q.-S.; Zhou, W.; Li, M. Extract from Dioscorea bulbifera L. rhizomes aggravate pirarubicin-induced cardiotoxicity by inhibiting the expression of P-glycoprotein and multidrug resistance-associated protein 2 in the mouse liver. Sci. Rep. 2021, 11, 19720.
  56. Pingili, R.B.; Pawar, A.K.; Challa, S.R. Systemic exposure of Paracetamol (acetaminophen) was enhanced by quercetin and chrysin co-administration in Wistar rats and in vitro model: Risk of liver toxicity. Drug Dev. Ind. Pharm. 2015, 41, 1793–1800.
  57. Okomolo, F.C.M.; Mbafor, J.T.; Bum, E.N.; Kouemou, N.; Kandeda, A.K.; Talla, E.; Dimo, T.; Rakotonirira, A.; Rakotonirira, S.V. Evaluation of the Sedative and Anticonvulsant Properties of Three Cameroonian Plants. Afr. J. Tradit. Complement. Altern. Med. 2011, 8, 181–190.
  58. Gupta, G.; Kazmi, I.; Afzal, M.; Rahman, M.; Saleem, S.; Ashraf, M.S.; Khusroo, M.J.; Nazeer, K.; Ahmed, S.; Mujeeb, M.; et al. Sedative, antiepileptic and antipsychotic effects of Viscum album L. (Loranthaceae) in mice and rats. J. Ethnopharmacol. 2012, 141, 810–816.
  59. Von Schoen-Angerer, T.; Madeleyn, R.; Kienle, G.; Kiene, H.; Vagedes, J. Viscum Album in the Treatment of a Girl with Refractory Childhood Absence Epilepsy. J. Child Neurol. 2015, 30, 1048–1052.
  60. Raish, M.; Ahmad, A.; Alkharfy, K.M.; Jan, B.L.; Mohsin, K.; Ahad, A.; Al-Jenoobi, F.I.; Al-Mohizea, A.M. Effects of Paeonia emodi on hepatic cytochrome P450 (CYP3A2 and CYP2C11) expression and pharmacokinetics of carbamazepine in rats. Biomed. Pharmacother. 2017, 90, 694–698.
  61. Raish, M.; Ahmad, A.; Ansari, M.A.; Alkharfy, K.M.; Ahad, A.; Al-Jenoobi, F.I.; Al-Mohizea, A.M.; Khan, A.; Ali, N. Effects of sinapic acid on hepatic cytochrome P450 3A2, 2C11, and intestinal P-glycoprotein on the pharmacokinetics of oral carbamazepine in rats: Potential food/herb-drug interaction. Epilepsy Res. 2019, 153, 14–18.
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Subjects: Toxicology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Jie Li
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Shuting Wang
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Fengjie Tian
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Shuang-Qing Zhang
,
Hongtao Jin
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Update Date: 20 Sep 2022
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