Inhibitory effect of flavonoids on multidrug and toxin extrusion protein 1 function: Implications for food/herb-drug interaction and drug-induced kidney injury.

Multidrug and toxin extrusion protein 1 (MATE1), an efflux transporter mainly expressed in renal proximal tubules, mediates the renal secretion of organic cationic drugs. The inhibition of MATE1 will impair the excretion of drugs into the tubular lumen, leading to the accumulation of nephrotoxic drugs in the kidney and consequently potentiating nephrotoxicity. Screening and identifying potent MATE1 inhibitors can predict or minimize the risk of drug-induced kidney injury. Flavonoids, a group of polyphenols commonly found in foodstuffs and herbal products, have been reported to cause transporter-mediated food/herb-drug interactions. Our objective was to investigate the inhibitory effects of flavonoids on MATE1 in vitro and in vivo and to assess the effects of flavonoids on cisplatin-induced kidney injury. Thirteen flavonoids exhibited significant transport activity inhibition (>50%) on MATE1 in MATE1-MDCK cells. Among them, the six strongest flavonoid inhibitors, including irisflorentin, silymarin, isosilybin, sinensetin, tangeretin, and nobiletin, markedly increased cisplatin cytotoxicity in these cells. In cisplatin-induced in vivo renal injury models, irisflorentin, isosilybin, and sinensetin also increased serum creatinine and blood urea nitrogen levels to different degrees, especially irisflorentin, which exhibited the most potent nephrotoxicity with cisplatin. The pharmacophore model indicated that the hydrogen bond acceptors at the 3, 5, and 7 positions may play a critical role in the inhibitory effect of flavonoids on MATE1. Our findings provide helpful information for predicting the potential risks of flavonoid-containing food/herb-drug interactions and avoiding the exacerbation of drug-induced kidney injury via MATE1 mediation.

Herb-drug interaction study of Yiqi Fumai lyophilized injection (YQFM) on pharmacokinetics of aspirin, nifedipine, and clopidogrel in rats.

Yiqi Fumai lyophilized injection (YQFM), a compound traditional Chinese medicine prescription derived from "Sheng Mai Powder," is approved for the treatment of cardiovascular diseases. YQFM is usually prescribed in combination with some Western medicines to treat patients, such as aspirin, nifedipine, and clopidogrel. However, the herb-drug interactions (HDIs) of YQFM are still unclear. We determined the effect of YQFM on drug metabolism-related CYP450 enzymes by in vitro assays. And the effects of YQFM on the pharmacokinetics of aspirin, nifedipine, or clopidogrel were analyzed in rats, as well as the effect of YQFM on the prothrombin time of aspirin or clopidogrel, to evaluate the safety and efficacy of co-administration. Our study indicated that the clinical dose of YQFM did not significantly influence the relevant CYP450 isoenzymes. Besides, YQFM had no effect on the pharmacokinetics of aspirin, nifedipine, or clopidogrel single and multiple administrations in rats. In pharmacodynamics study, YQFM also had no impact on prothrombin time of aspirin or clopidogrel. Based on the results of pharmacogenomics, pharmacokinetics, and pharmacodynamics, the HDIs of YQFM have a good safety profile, and the combination with the above three drugs might have synergistic effects due to the different efficacy of YQFM-quality markers.

Herb-drug interactions: A short review on central and peripheral nervous system drugs.

Herbal medicines are widely perceived as natural and safe remedies. However, their concomitant use with prescribed drugs is a common practice, often undertaken without full awareness of the potential risks and frequently without medical supervision. This practice introduces a tangible risk of herb-drug interactions, which can manifest as a spectrum of consequences, ranging from acute, self-limited reactions to unpredictable and potentially lethal scenarios. This review offers a comprehensive overview of herb-drug interactions, with a specific focus on medications targeting the Central and Peripheral Nervous Systems. Our work draws upon a broad range of evidence, encompassing preclinical data, animal studies, and clinical case reports. We delve into the intricate pharmacodynamics and pharmacokinetics underpinning each interaction, elucidating the mechanisms through which these interactions occur. One pressing issue that emerges from this analysis is the need for updated guidelines and sustained pharmacovigilance efforts. The topic of herb-drug interactions often escapes the attention of both consumers and healthcare professionals. To ensure patient safety and informed decision-making, it is imperative that we address this knowledge gap and establish a framework for continued monitoring and education. In conclusion, the use of herbal remedies alongside conventional medications is a practice replete with potential hazards. This review not only underscores the real and significant risks associated with herb-drug interactions but also underscores the necessity for greater awareness, research, and vigilant oversight in this often-overlooked domain of healthcare.

Phytotherapy in psychiatry: why psychiatrists should know about it.

There is a substantial use of Complementary and Alternative Medicine (CAM) among both the general population and psychiatric patients, with only a minority of these users disclosing this information to their healthcare providers, including physicians and psychiatrists. This widespread use of CAM can impact positively or negatively on the clinical outcomes of psychiatric patients, and it is often done along with conventional medicines. Among CAM, phytotherapy has a major clinical relevance due to the introduction of potential adverse effects and drug interactions. Thus, the psychiatrist must learn about phytotherapy and stay up-to-date with solid scientific knowledge about phytotherapeutics/herbal medicines to ensure optimal outcomes for their patients. Furthermore, questions about herbal medicines should be routinely asked to psychiatric patients. Finally, scientifically sound research must be conducted on this subject.

Pharmacokinetic and pharmacodynamic herb-drug interactions of common over-the-counter pain medications.

Pain is one of the most common reasons for seeking medical intervention, and self-medication with over-the-counter medications and/or traditional herbal remedies has become increasingly popular. In this review, original articles on understanding possible herb-drug interactions between traditional herbs and four major pain medications-acetaminophen, aspirin, ibuprofen and naproxen-are compiled and analyzed. In terms of analytical methods, high-performance liquid chromatography using an isocratic eluent system coupled to biological sample clean-up is the most common, while a wide variety of detectors have been observed, including a photodiode array, variable wavelength detector, electrochemical detector and tandem mass spectrometer. Both synergistic and anti-synergistic effects were observed for acetaminophen and aspirin, while only synergistic effects have been found for naproxen. Currently, no interactions have been reported for ibuprofen.

Evaluation of herb-drug interactions between compound Danshen dripping pills and clopidogrel based on the pharmacokinetics and pharmacodynamics in rats.

Compound Danshen dripping pills (CDDP), a well-known traditional Chinese medicine, is widely used to prevent and treat cardiovascular diseases. CDDP is usually prescribed in combination with clopidogrel (CLP), but the herb-drug interactions are rarely reported. This study evaluated the effects of CDDP on the pharmacokinetics and pharmacodynamics of coadministered CLP, and ensured the safety and efficacy of their usage. The trial design included a single-dose administration and multidose test for 7 consecutive days. Wistar rats received CLP alone or CLP combined with CDDP. After the final dose, plasma samples were collected at various time points, and the active metabolite H4 of CLP was analyzed by ultrafast liquid chromatography coupled with triple quadrupole tandem mass spectrometry. The main pharmacokinetic parameters of Cmax (maximum [or peak] serum concentration), Tmax (peak plasma time), t1/2 (half-time), AUC0-∞ (area under the concentration-time curve from dosing (time 0) to infinite time), and AUC0-t (area under the concentration-time curve from dosing [time 0] to time t) were calculated using the non-compartment model. In addition, prothrombin time, activated partial thromboplastin time, bleeding time, and adenosine diphosphate-induced platelet aggregation were evaluated for anticoagulation and antiplatelet aggregation activity. In this study, we found that CDDP had no significant effect on the metabolism of CLP in rats. In pharmacodynamic studies, the combination group showed significant synergistic antiplatelet activity compared with the CLP or CDDP groups alone. Based on pharmacokinetic and pharmacodynamic results, CDDP and CLP have synergistic effects on antiplatelet aggregation and anticoagulation.

Recent Advances in Synthetic Drugs and Natural Actives Interacting with OAT3.

Organic anion transporter 3 (OAT3) is predominantly expressed in the kidney and plays a vital role in drug clearance. Consequently, co-ingestion of two OAT3 substrates may alter the pharmacokinetics of the substrate. This review summarizes drug-drug interactions (DDIs) and herbal-drug interactions (HDIs) mediated by OAT3, and inhibitors of OAT3 in natural active compounds in the past decade. This provides a valuable reference for the combined use of substrate drugs/herbs for OAT3 in clinical practice in the future and for the screening of OAT3 inhibitors to avoid harmful interactions.

Effects of Apigenin on Pharmacokinetics of Dasatinib and Probable Interaction Mechanism.

Dasatinib (DAS), a narrow-therapeutic index drug, Bcr-Abl, and Src family kinases multitarget inhibitor have been approved for chronic myelogenous leukemia (CML) and Ph-positive acute lymphocytic leukemia (Ph+ ALL). Apigenin (APG) has a long history of human usage in food, herbs, health supplements, and traditional medicine, and it poses low risk of damage. The concomitant use of APG containing herbs/foods and traditional medicine may alter the pharmacokinetics of DAS, that probably lead to possible herb-drug interactions. The pharmacokinetic interaction of APG pretreatment with DAS in rat plasma following single and co-oral dosing was successfully deliberated using the UPLC-MS/MS method. The in vivo pharmacokinetics and protein expression of CYP3A2, Pgp-MDR1, and BCPR/ABCG2 demonstrate that APG pretreatment has potential to drastically changed the DAS pharmacokinetics where escalation in the Cmax, AUC(0-t), AUMC(0-inf_obs), T1/2, Tmax, and MRT and reduction in Kel, Vd, and Cl significantly in rats pretreated with APG 40 mg/kg, thus escalating systemic bioavailability and increasing the rate of absorption via modulation of CYP3A2, Pgp-MDR1, and BCPR/ABCG2 protein expression. Therefore, the concomitant consumption of APG containing food or traditional herb with DAS may cause serious life-threatening drug interactions and more systematic clinical study on herb-drug interactions is required, as well as adequate regulation in herbal safety and efficacy.

Herb-drug interaction: Effect of sinapic acid on the pharmacokinetics of dasatinib in rats.

Dasatinib (DAS) is a narrow therapeutic index drug and novel oral multitarget inhibitor of tyrosine kinase and approved for the first-line therapy for chronic myelogenous leukemia (CML) and Philadelphia chromosome (Ph + ) acute lymphoblastic leukemia (ALL). DAS, a known potent substrate of cytochrome (CYP) 3A, P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) and is subject to auto-induction. The dietary supplementation of sinapic acid (SA) or concomitant use of SA containing herbs/foods may alter the pharmacokinetics as well as pharmacodynamics of DAS, that may probably lead to potential interactions. Protein expression in rat hepatic and intestinal tissues, as well as the in vivo pharmacokinetics of DAS and the roles of CYP3 A2 and drug transporters Pgp-MDR1 and BCPR/ABCG2, suggested a likely interaction mechanism. The single dose of DAS (25 mg/kg) was given orally to rats with or without SA pretreatment (20 mg/kg p.o. per day for 7 days, n = 6). The plasma concentration of DAS was estimated by using Ultra-High-Performance Liquid Chromatography Mass spectrometry (UHPLC-MS/MS). The in vivo pharmacokinetics and protein expression study demonstrate that SA pretreatment has potential to alter the DAS pharmacokinetics. The increase in Cmax, AUC and AUMC proposes increase in bioavailability and rate of absorption via modulation of CYP3 A2, PgP-MDR1 and BCPR/ABCG2 protein expression. Thus, the concomitant use of SA alone or with DAS may cause serious life-threatening drug interactions.

Drug interaction potential of Ankaferd blood stopper® in human hepatocarcinoma cells.

BACKGROUND: Ankaferd blood stopper® (ABS) is an herbal extract consisting of mixtures of Alpinia officinarum, Gycyrrhiza glabra, Vitis vinifera, Thymus vulgaris, and Urtica dioica plants and has been used in recent years in Turkish medicine as a hemostatic agent. Despite its extensive usage, there is no information available about the drug interaction in HepG2 cells. The current work evaluated the effect of ABS on the expression of CYP1A1-1A2, CYP2E1, and CYP3A4 isozymes that are primarily involved in drug and carcinogen metabolism. METHODS: We selected HepG2 cells as in vitro cellular models of the human liver. The cells were treated with different concentrations of ABS [0.25%-40% (v/v)]. A crystal violet staining assay was used to determine the cytotoxicity of ABS. We examined drug-metabolizing enzymes, including 7-ethoxyresorufin O-deethylase (CYP1A1), 7-methoxyresorufin O-demethylase (CYP1A2), aniline 4-hydroxylase (CYP2E1), and erythromycin N-demethylase (CYP3A4), in vitro in HepG2 cells. The expression (mRNA, protein) levels of drug-metabolizing enzymes were analyzed by qPCR and Western blotting, respectively. RESULTS: The EC05 and EC10 values for ABS were 0.37% and 0.52% (v/v), respectively. Therefore, 0.37% and 0.52% (v/v) doses were used for the remaining portion of this study. Investigation of the expression and activity levels revealed that CYP1A1-1A2, CYP2E1, and CYP3A4 activities were not affected by ABS significantly, with qPCR and Western blot results corroborating this result. DISCUSSION: Our study found that the activity, mRNA, and protein expression levels of CYP isozymes did not change with the application of ABS, suggesting that when humans are exposed to ABS, there may not be any risk associated with clinical drug toxicity, cancer formation, and drug metabolism disorders in humans.

Inhibition of drug-metabolizing enzymes by Jingyin granules: implications of herb-drug interactions in antiviral therapy.

Jingyin granules, a marketed antiviral herbal medicine, have been recommended for treating H1N1 influenza A virus infection and Coronavirus disease 2019 (COVID-19) in China. To fight viral diseases in a more efficient way, Jingyin granules are frequently co-administered in clinical settings with a variety of therapeutic agents, including antiviral drugs, anti-inflammatory drugs, and other Western medicines. However, it is unclear whether Jingyin granules modulate the pharmacokinetics of Western drugs or trigger clinically significant herb-drug interactions. This study aims to assess the inhibitory potency of the herbal extract of Jingyin granules (HEJG) against human drug-metabolizing enzymes and to clarify whether HEJG can modulate the pharmacokinetic profiles of Western drug(s) in vivo. The results clearly demonstrated that HEJG dose-dependently inhibited human CES1A, CES2A, CYPs1A, 2A6, 2C8, 2C9, 2D6, and 2E1; this herbal medicine also time- and NADPH-dependently inhibited human CYP2C19 and CYP3A. In vivo tests showed that HEJG significantly increased the plasma exposure of lopinavir (a CYP3A-substrate drug) by 2.43-fold and strongly prolonged its half-life by 1.91-fold when HEJG (3 g/kg) was co-administered with lopinavir to rats. Further investigation revealed licochalcone A, licochalcone B, licochalcone C and echinatin in Radix Glycyrrhizae, as well as quercetin and kaempferol in Folium Llicis Purpureae, to be time-dependent CYP3A inhibitors. Collectively, our findings reveal that HEJG modulates the pharmacokinetics of CYP substrate-drug(s) by inactivating CYP3A, providing key information for both clinicians and patients to use herb-drug combinations for antiviral therapy in a scientific and reasonable way.

Effect of turmeric supplementation on the pharmacokinetics of paclitaxel in breast cancer patients: A study with population pharmacokinetics approach.

Turmeric is one of the most used herbal supplements among cancer patients. It reportedly modulates the function of CYP450 enzymes and drug transporters. This study investigates the effect of turmeric on the pharmacokinetics of paclitaxel in breast cancer patients. This is a prospective longitudinal study with 60 breast cancer patients on treatment with single-agent paclitaxel and turmeric. The patients were followed up for two consecutive chemotherapy cycles, and their blood samples were collected, first without turmeric (first cycle) and the next after a 21-day concomitant administration of 2 g/day turmeric (second cycle). Plasma samples were quantified for paclitaxel concentration using High Performance Liquid Chromatograph with UV detector (HPLC-UV) method. The sparse concentration-time data of paclitaxel were subjected to population pharmacokinetic modeling, and then noncompartmental analysis (NCA) was performed on the simulated data to estimate the pharmacokinetic parameters of paclitaxel, before and after turmeric supplementation, for comparisons. The population pharmacokinetic parameters of paclitaxel differed from before to after turmeric supplementation. NCA of simulated concentration-time profiles showed a statistically significant reduction of 7.7% and 12.1% in AUCinf and Cmax, respectively. Given the small magnitude of the changes in pharmacokinetic parameters, the observed changes are not clinically relevant. Thereby, turmeric at the recommended dose can be combined safely with paclitaxel.

Molecular dynamics simulation and in vitro evaluation of herb-drug interactions involving dietary polyphenols and CDK inhibitors in breast cancer chemotherapy.

Dietary polyphenols such as quercetin and curcumin have been extensively administered to patients with cancer in the form of herbal supplements. They may have a synergistic anticancer effect; however, a risk of pharmacokinetic interactions with selective CDK-4/6 inhibitors that are metabolized by the CYP3A4 enzyme exists. Considering these pharmacokinetic aspects, the current study examined the effects of curcumin and quercetin on human CYP3A4 to ascertain CYP3A4-mediated herb-drug interactions with CDK inhibitors. In this study, using in silico methods and CYP3A4 inhibition kinetics in human liver microsomes and recombinant CYP3A4 enzymes, the effects of concentration-dependent inhibition of CYP3A4 by quercetin and curcumin on CDK inhibitors metabolism were examined. Based on our in-silico docking findings, curcumin and quercetin were considerably bound to CYP3A4 protein and displace CDK inhibitors from the CYP3A4 substrate binding domain. The IC50 values of curcumin and quercetin were 16.10 and 0.05 µM, respectively, for CYP3A4-mediated 1'-hydroxylation of midazolam. The dietary polyphenols prolonged the in vitro half-life of palbociclib and ribociclib by 6.4-fold and decreased their intrinsic microsomal clearance by approximately 4.6 times. Our findings indicate that curcumin and quercetin effectively cause herb-drug interactions and should be cautiously used to avoid therapeutic failure.

Pharmacokinetic Herb-Drug Interactions of Glipizide with Andrographis paniculata (Burm. f.) and Andrographolide in Normal and Diabetic Rats by Validated HPLC Method.

Co-administered medicinal herbs can modify a drug's pharmacokinetics (PK), effectiveness, and toxicity. Andrographis paniculata (Burm. f.) ethanolic extract (APE) and andrographolide (AND) (a potent CYP2C9 inducer/inhibitor) can alter the pharmacokinetic parameters of glipizide (GLZ). This study aimed to determine the potential pharmacokinetics of herb−drug interactions between GLZ and APE/AND in the plasma of normal and diabetic rats using the HPLC bioanalysis method. The glipizide bioanalytical method established with RP-HPLC/UV instrument was validated following the EMA guidelines. GLZ was administered alone and in combination with APE or AND to normal and diabetic rats. The GLZ pharmacokinetic parameters were estimated according to the correlation between concentration and sampling time using the PK solver program. A simple and rapid GLZ bioanalysis technique with a lower limit of quantitation of 25 ng/mL was developed and presented the following parameters: accuracy (error ≤ 15%), precision (CV ≤ 15%), selectivity, stability, and linearity (R2 = 0.998) at concentrations ranging 25−1500 ng/mL. APE administration significantly improved the Cmax and AUC0−t/AUC0−∞ GLZ values in normal and diabetic rats (p < 0.05). AND significantly reduced the bioavailability of GLZ in diabetic rats with small values of T 1/2, Cmax, and AUC0−t/AUC0−∞ (p < 0.05). This combination can be considered in administering medications because it can influence the pharmacological effects of GLZ.

Food constituent- and herb-drug interactions in oncology: Influence of quantitative modelling on Drug labelling.

AIMS: Herbal products, spices and/or fruits are perceived as inherently healthy; for instance, St. John's wort (SJW) is marketed as a natural antidepressant and patients often self-administer it concomitantly with oncology medications. However, food constituents/herbs can interfere with drug pharmacokinetics, with risk of altering pharmacodynamics and efficacy. The objective of this work was to develop a strategy to prioritize herb- or food constituent-drug interactions (FC-DIs) to better assess oncology drug clinical risk. METHODS: Physiologically based pharmacokinetic (PBPK) models were developed by integrating in vitro parameters with the clinical pharmacokinetics of food constituents in grapefruit juice (bergamottin), turmeric (curcumin) or SJW (hyperforin). Perpetrator files were linked to verified victim PBPK models through appropriate interaction mechanisms (cytochrome P450 3A, breast cancer resistance protein, P-glycoprotein) and applied in prospective PBPK simulations to inform the likelihood and magnitude of changes in exposure to osimertinib, olaparib or acalabrutinib. RESULTS: Reported FC-DIs with oncology drugs were well recovered, with absolute average fold error values of 1.10 (bergamottin), 1.05 (curcumin) and 1.01 (hyperforin). Prospective simulations with grapefruit juice and turmeric showed clinically minor to insignificant changes in exposure (<1.50-fold) to acalabrutinib, osimertinib and olaparib, but predicted 1.57-fold FC-DI risk between acalabrutinib and curcumin. Moderate DDI risk was expected when acalabrutinib, osimertinib or olaparib were dosed with SJW. CONCLUSIONS: A model-informed decision tree based on mechanistic understanding of transporter and/or enzyme-mediated FC-DI is proposed based on bergamottin, curcumin and hyperforin FC-DI clinical data. Adopting this quantitative modelling approach should streamline herbal product safety assessments, assist in FC-DI management, and ultimately promote safe clinical use of oncology drugs.

Pharmacokinetics of gallic acid and protocatechuic acid in humans after dosing with Relinqing (RLQ) and the potential for RLQ-perpetrated drug-drug interactions on organic anion transporter (OAT) 1/3.

CONTEXT: Relinqing granules (RLQ) are being used alone or in combination with antibacterial drugs to treat urological disorders. OBJECTIVE: This study investigates the pharmacokinetics of RLQ in humans and the potential for RLQ-perpetrated interactions on transporters. MATERIALS AND METHODS: Twelve healthy subjects (six women and six men) participated to compare single- and multiple-dose pharmacokinetics of RLQ. In the single-dose study, all 12 subjects received 8 g of RLQ orally. After a 7-d washout period, the subjects received 8 g of RLQ for seven consecutive days (t.i.d.) and then a single dose. Gallic acid (GA) and protocatechuic acid (PCA) in plasma and urine samples were analysed using LC-MS/MS. The transfected cells were used to study the inhibitory effect of GA (50-5000 µg/L) and PCA (10-1000 µg/L) on transporters OAT1, OAT3, OCT2, OATP1B1, P-gp and BCRP. RESULTS: GA and PCA were absorbed into the blood within 1 h after administration and rapidly eliminated with a half-life of less than 2 h. The mean peak concentrations of GA (102 and 176 µg/L) and PCA (4.54 and 7.58 µg/L) were lower in males than females, respectively. The 24 h urine recovery rates of GA and PCA were about 10% and 5%, respectively. The steady-state was reached in 7 d without accumulation. GA was a potent inhibitor of OAT1 (IC50 = 3.73 µM) and OAT3 (IC50 = 29.41 µM), but not OCT2, OATP1B1, P-gp or BCRP. DISCUSSION AND CONCLUSIONS: GA and PCA are recommended as PK-markers in RLQ-related pharmacokinetic and drug interaction studies. We should pay more attention to the potential for RLQ-perpetrated interactions on transporters.

Goldenseal (Hydrastis canadensis L.) and its active constituents: A critical review of their efficacy and toxicological issues.

Goldenseal (Hydrastis canadensis L.) is a medicinal plant widely used in various traditional systems of medicine and as a food supplement. It has been traditionally used by Native Americans as a coloring agent and as medicinal remedy for common diseases and conditions like wounds, digestive disorders, ulcers, skin and eye ailments, and cancer. Over the years, goldenseal has become a popular food supplement in the USA and other regions. The rhizome of this plant has been used for the treatment of a variety of diseases including, gastrointestinal disorders, ulcers, muscular debility, nervous prostration, constipation, skin and eye infections, cancer, among others. Berberine is one of the most bioactive alkaloid that has been identified in different parts of goldenseal. The goldenseal extract containing berberine showed numerous therapeutic effects such as antimicrobial, anti-inflammatory, hypolipidemic, hypoglycemic, antioxidant, neuroprotective (anti-Alzheimer's disease), cardioprotective, and gastrointestinal protective. Various research finding suggest the health promoting effects of goldenseal components and their extracts. However, few studies have also suggested the possible neurotoxic, hepatotoxic and phototoxic activities of goldenseal extract and its alkaloids. Thus, large randomized, double-blind clinical studies need to be conducted on goldenseal supplements and their main alkaloids to provide more evidence on the mechanisms responsible for the pharmaceutical activity, clinical efficacy and safety of these products. Thus, it is very important to review the scientific information about goldenseal to understand about the current scenario.

Potential for pharmacokinetic interactions between Schisandra sphenanthera and bosutinib, but not imatinib: in vitro metabolism study combined with a physiologically-based pharmacokinetic modelling approach.

AIMS: This study aimed to investigate the potential interaction between Schisandra sphenanthera, imatinib and bosutinib combining in vitro and in silico methods. METHODS: In vitro metabolism of imatinib and bosutinib using recombinant enzymes and human liver microsomes were investigated in the presence and absence of Schisandra lignans. Physiologically-based pharmacokinetic (PBPK) models for the lignans accounting for reversible and mechanism-based inhibitions and induction of CYP3A enzymes were built in the Simcyp Simulator (version 17) and evaluated for their capability to predict interactions with midazolam and tacrolimus. Their potential effect on systemic exposures of imatinib and bosutinib were predicted using PBPK in silico simulations. RESULTS: Schisantherin A and schisandrol B, but not schisandrin A, potently inhibited CYP3A4-mediated metabolism of imatinib and bosutinib. All three compounds showed a strong reversible inhibition on CYP2C8 enzyme with ki of less than 0.5 µmol L-1 . The verified PBPK models were able to describe the increase in systemic exposure of midazolam and tacrolimus due to co-administration of S. sphenanthera, consistent with the reported changes in the corresponding clinical interaction study (AUC ratio of 2.0 vs 2.1 and 2.4 vs 2.1, respectively). The PBPK simulation predicted that at recommended dosing regimens of S. sphenanthera, co-administration would result in an increase in bosutinib exposure (AUC ratio 3.0) but not in imatinib exposure. CONCLUSION: PBPK models for Schisandra lignans were successfully developed. Interaction between imatinib and Schisandra lignans was unlikely to be of clinical importance. Conversely, S. sphenanthera at a clinically-relevant dose results in a predicted three-fold increase in bosutinib systemic exposure.

Inhibition of UDP-glucuronosyltransferases by different furoquinoline alkaloids.

Herbs are often administered in combination with therapeutic drugs, raising the possibility for herb-drug interactions (HDIs). Furoquinoline alkaloids are found in Rutaceae plants, which are structurally similar and have many medicinal properties. This study aims to investigate the inhibition of four furoquinoline alkaloids on the activity of UDP-glucuronosyltransferases (UGTs).The recombinant UGTs-catalyzed glucuronidation metabolism of 4-methylumbelliferone (4-MU) was utilized to investigate the inhibition potential. Inhibition type and parameters were determined, and in silico docking was employed to elucidate the inhibition difference of furoquinoline alkaloids towards UGTs.Dictamine, haplopine, γ-fagarine and skimmianine strongly inhibited UGT1A3, UGT1A7, UGT1A9 and UGT2B4, respectively. Among them, dictamnine inhibited more than 70% of the four UGTs. Inhibition kinetics determination showed that they all exerted competitive inhibition, and the inhibition kinetic constant (Ki) was determined to be 8.3, 7.2, 3.7 and 33.9 µM, respectively. In vitro-in vivo extrapolation (IVIVE) was employed to demonstrate the inhibition possibility for four alkaloids. Skimmianine was proved to be more suitable for clinical application. In silico docking study indicated that the hydrophobic interactions played a key role in the inhibition of furoquinoline alkaloids towards three of the four UGTs. In conclusion, monitoring the interactions between furoquinoline alkaloids and drugs mainly undergoing UGTs-catalyzed metabolism is necessary.

Comparison of eight screening tools to detect interactions between herbal supplements and oncology agents.

INTRODUCTION: Patients with cancer are increasingly using herbal supplements, unaware that supplements can interact with oncology treatment. Herb-drug interaction management is critical to ensure optimal treatment outcomes. Several screening tools exist to detect drug-drug interactions, but their performance to detect herb-drug interactions is not known. This study compared the performance of eight drug-drug interaction screening tools to detect herb-drug interaction with anti-cancer agents. METHODS: The herb-drug interaction detection performance of four subscription (Micromedex, Lexicomp, PEPID, Facts & Comparisons) and free (Drugs.com, Medscape, WebMD, RxList) drug-drug interaction tools was assessed. Clinical relevance of each herb-drug interaction was determined using Natural Medicine and each drug-drug interaction tool. Descriptive statistics were used to calculate sensitivity, specificity, positive predictive value, and negative predictive value. Linear regression was used to compare performance between subscription and free tools. RESULTS: All tools had poor sensitivity (<0.20) for detecting herb-drug interaction. Lexicomp had the highest positive predictive value (0.98) and best overall performance score (0.54), while Medscape was the best performing free tool (0.52). The worst subscription tools were as good as or better than the best free tools, and as a group subscription tools outperformed free tools on all metrics. Using an average subscription tool would detect one additional herb-drug interaction for every 10 herb-drug interactions screened by a free tool. CONCLUSION: Lexicomp is the best available tool for screening herb-drug interaction, and Medscape is the best free alternative; however, the sensitivity and performance for detecting herb-drug interaction was far lower than for drug-drug interactions, and overall quite poor. Further research is needed to improve herb-drug interaction screening performance.