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Wuzhi tablet (WZ) is a prescribed herbal medicine extracted from Schisandra sphenanthera, which is widely used to protect the liver injury and drug-induced hepatotoxicity in clinical practices. Previous studies showed that WZ significantly increased the blood concentrations of tacrolimus, cyclosporine A, paclitaxel by inhibiting the cytochrome P450 3A (CYP3A)-mediated metabolism. CYP3A4 and CYP3A5 are the most important isoenzymes among the CYP3A subfamily. However, there are some differences in the catalytic and inhibitory activities between CYP3A4 and CYP3A5, which may lead to different risk of drug-drug and herb-drug interactions, and the risks may be further amplified in vivo. Currently, few reports have compared the herbal medicine inhibitory effects between CYP3A4 and CYP3A5 mediated metabolic reactions. Therefore, detailing the inhibitory effect of WZ on CYP3A4 and CYP3A5 will help understand and predict the potential herb-drug interaction. The results showed that WZ inhibited CYP3A4 and CYP3A5 in a NADPH-, time- and concentration- dependent manner. WZ showed more potent inhibition on CYP3A5 than CYP3A4. Cautions warranted when combining WZ with other therapeutic drugs to avoid the potential herb-drug interaction.
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Alpinia officinarum Hance of the Chinese traditional herb for the treatment of emesis,abdominal pain and diarrhea has been used to counteract gastric disease induced by indomethacin in rats without obvious side effects.However,the role of herb-drug interaction between indomethacin and A.officinarum based on pharmacokinetic,tissue distribution and excretion still remains unknown.In this study,an ultra-fast liquid-tandem mass spectrometry(UFLC-MS/MS)method was developed for simultaneous determina-tion of indomethacin and its three metabolites,O-desmethylindomethacin(ODI),deschlor-obenzoylindomethacin(NDI)and indomethacin acyl-β-D-glucuronide(IDAβG)by oral administration of indomethacin solution with and without the ethanolic extract of A.officinarum and applied to comparative pharmacokinetic,tissue distribution and excretion studies.Our results clarified that oral administration of A.officinarum produced significant alterations in the pharmacokinetic parameters of indomethacin.And the pharmacokinetic interaction between indomethacin and A.officinarum reduced the systemic exposure of indomethacin and increased its elimination.Tissue distribution results demonstrated that co-administration of A.Officinarum could not reduce the accumulation of indo-methacin in the target tissue of the stomach,but could accelerate the excretions of indomethacin and its three metabolites including ODI,NDI and IDAβG in the bile and feces of rats in the excretion study.Therefore,A.Officinarum might have a gastrointestinal protective effect through the interaction role with indomethacin based on the pharmacokinetics and excretion in rats.
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Seventy-nine injectable herb extractions have been approved by the Chinese Food and Drug Administration (CFDA) and are frequently administered intravenously for various diseases. Unfortunately, herb-drug interactions are under-investigated and sometimes overlooked in the clinic. In the present investigation the in vitro inhibition of 9 drug metabolizing enzymes including CYP1A, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A was assessed using an appropriate probe substrate for each enzyme with human liver microsomes. Metabolite formation was quantified using a validated and sensitive high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The IC50 of each herb extract was estimated using a concentration range from 5% to 0.5%, and the time-dependent inhibition of the nine CYP450 isoenzymes was also determined. Of the 79 approved iv herb injectables, 37 inhibited CYP1A, 24 inhibited CYP2A6, 41 inhibited CYP2B6, 36 inhibited CYP2C8, 31 inhibited CYP2C9, 41 inhibited CYP2C19, 13 inhibited CYP2D6, 25 inhibited CYP2E1, and 42 inhibited CYP3A with 50% or greater inhibition at a test concentration of 5% (v/v). IC50 differences were noted between pre-incubation or co-incubation assays with HLM for 30 min, with the time-dependent inhibitory (TDI) effects were observed with 2 injectables on CYP1A, 5 injectables on CYP2A6, 5 injectables on CYP2B6, 6 injectables on CYP2C8, 1 injectable on CYP2D6 and 6 injectables on CYP3A. Collectively, the results demonstrate that potential herb-drug interactions (HDIs) can occur with the concomitant use of herb injectables and prescription drugs that are cleared by CYP450 enzymes, and further investigation is warrant for the clinical relevance of these interactions.
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Danhong injection (DHI) and ceftriaxone sodium were used in combination based on their experimental uses in clinic. This study was designed to investigate the impact of ceftriaxone on pharmacokinetics and pharmacodynamics of the phenolic acids from DHI. After administration of DHI for 7 d, ceftriaxone (CFTX) was combined with DHI for the next 7 d in adult male Sprague-Dawley (SD) rats. All the drugs were administered through caudal vein. UHPLC-TQ-MS was applied in determining the plasma concentration of p-coumaric acid (p-CA), salvianolic acid D (SaD), rosmarinic acid (RA) and salvianolic acid B (SaB). The pharmacokinetic parameters of the combination group or the Danhong injection alone group were calculated by statistical moment method, Cmax and the average of the area under the curve AUC0-t using 90% confidence interval of the bioequivalence and bioavailability degree module in DAS 3.2.8 statistic software. The results showed that Cmax of p-CA, SaD, RA and SaB were unqualified within 90% confidence intervals for bioequivalence statistics. And the results showed that AUC0-t of SaD, RA and SaB within 90% confidence intervals for bioequivalence statistics were unqualified. There were no significant difference in the tmax (P>0.05). The results of anticoagulation in vivo showed that the international normalized ratio (INR), prothrombin time (PT), thrombin time (TT) and activated partial thromboplastin time (APTT) were significantly increased when combined with CFTX (P<0.05 or P<0.01). The results in antithrombotic effects revealed that the thromboxane B2 (TXB2) level in serum was significantly decreased (P<0.01) in the combination group compared with Danhong injection alone. However, there was no significant difference in antiplatelet effects. These results suggest that CFTX may enhance the anticoagulation and antithrombotic effects of DHI through altering pharmacokinetics and pharmacodynamics in SD rats.
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This study was aimed to explore the effects of tannins in Galla Chinensis on rifampicin in vivo. In the experiment in vitro, UV spectrophotometry and high performance liquid chromatography (HPLC) were used to investigate the solubility of rifampin in pH 1.3, 6.8, artificial gastric juice environment and artificial intestinal fluid environment as well as the effects of tannins on solubility of rifampin in the above conditions. In the experiment in vivo, the process of rifampicin was studied after intragastric administration of rifampicin and rifampicin+ tannins in Galla Chinensis, and then the pharmacokinetic parameters were calculated. The results showed that rifampicin was constantly precipitated in the artificial gastric juice environment over time, and nearly 85% of the rifampicin was precipitated after 6 hours; it showed a good solubility in the artificial intestinal juice environment. After adding the said tannins, the concentration of rifampicin was decreased significantly in both environments, and the concentration of rifampicin in artificial intestinal juice remained relatively stable, while that in artificial gastric juice remained the original downward trend. The pharmacokinetic parameters displayed that as compared with rifampicin alone, AUC0-t and Cmax were decreased significantly, MRT0-t slowed down significantly, Tmax doubled to 7.0 h and the bioavailability was only 31.65% in rifampicin + tannins in Galla Chinensis group. The experiment indicated rifampicin had a poor solubility in acidic environment and the decrease of bioavailability of rifampicin when in combination with tannin was mainly due to the reduction of rifampicin solubility in intestinal tract by complexation of rifampicin with tannin, thus affecting its absorption in intestinal tract. Therefore, rifampicin and the Chinese herbal medicines or Chinese patent medicines rich in tannin should not be taken simultaneously.
Subject(s)
Drugs, Chinese Herbal , Rifampin , Pharmacokinetics , TanninsABSTRACT
<p><b>OBJECTIVE</b>To evaluate the potential pharmacokinetic interactions of the anticancer agent gefitinib (Iressa®) and the oriental medications Guipi Decoction (, GPD, Guibi-tang in Korean) and Bawu Decoction (, BWD, Palmul-tang in Korean).</p><p><b>METHODS</b>Methylcellulose (MC, control), GPD (1,200 mg/kg), or BWD (6,000 mg/kg) was orally administered to rats either as a single dose or multiple doses prior to gefitinib administration. To examine the effects of a single dose of the herbal medicines, gefitinib (10 mg/kg) was orally administered after 5 min or 1 h of MC or the herbal medicine pretreatments. To examine the effects of the multiple doses of the herbal medicines, gefitinib (10 mg/kg) was orally administered following 7 consecutive days of the administration of MC or each herbal medicine. The plasma concentrations of gefitinib were determined with liquid chromatography-tandem mass spectrometry assay. The plasma concentration-time profiles of gefitinib were analyzed with a noncompartmental analysis.</p><p><b>RESULTS</b>Gefitinib was rapidly absorbed and showed a monoexponential decline with an elimination half-life of 3.7-4.1 h. The pharmacokinetics of gefitinib was not affected by GPD pretreatment. However, a significantly lower maximum plasma concentration (C, P<0.05) and area under the curve (P<0.05), and a delayed time to reach C (T, P<0.01) were observed in both single- and multipledose BWD-pretreated rats compared with the control rats.</p><p><b>CONCLUSIONS</b>BWD and not GPD might delay and interfere with gefitinib absorption. Further evaluations of the clinical significance of these findings are needed.</p>
Subject(s)
Animals , Male , Chromatography, Liquid , Dose-Response Relationship, Drug , Drugs, Chinese Herbal , Pharmacology , Quinazolines , Blood , Pharmacokinetics , Rats, Sprague-Dawley , Tandem Mass Spectrometry , Time FactorsABSTRACT
OBJECTIVE To investigate the inhibitory effect of eight lignan compounds of Fructus Schisandrae chinensis in vitro on carboxylesterase 2 (CES2) and to estimate the herb-drug interaction (HDI) risks of strong CES2 inhibitors selected from the above compounds. METHODS Fluorescein diacetate (FD) was employed as a specific fluorescent probe of CES2. The residual activity of CES2 was detected in human liver microsomes after the intervention with deoxyschizandrin, schisanhenol, schisantherin E, schisandrol A, schisandrol B, gomisin J, gomisin G, and gomisin O at 37℃ for 10 min, respectively. 1% DMSO served as control. Residual activity of CES2 was assessed with metabolite production of FD detected by fluorescent intensity, combined with IC50 values of the above compounds to predict HDI risks between lignans and CES2-metabolizing drugs. RESULTS Compared with control group, the activity of CES2 was significantly inhibited by deoxyschizandrin and schisanhenol (P<0.01), with IC50 values of 8.06 μmol · L- 1 and 8.91 μmol · L- 1, respectively. The other six lignans compounds exhibited mild inhibitory effect on CES2. HDI risk prediction of deoxyschizandrin or schisanhenol indicated that exposure of CES2-metabolizing drugs might increase 11.24 and 0.40 times, respectively. CONCLUSION Deoxyschizandrin and schisanhenol exhibit strong inhibitory effects against CES2 in vitro so that potential HDI risks should be taken into account during administration of drugs containing Fructus Schisandrae chinensis.
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Ferulic acid (FA) is an active component of herbal medicines. One of the best documented activities of FA is its antioxidant property. Moreover, FA exerts antiallergic, anti-inflammatory, and hepatoprotective effects. However, the metabolic pathways of FA in humans remain unclear. To identify whether human CYP or UGT enzymes are involved in the metabolism of FA, reaction phenotyping of FA was conducted using major CYP-selective chemical inhibitors together with individual CYP and UGT Supersomes. The CYP- and/or UGT-mediated metabolism kinetics were examined simultaneously or individually. Relative activity factor and total normalized rate approaches were used to assess the relative contributions of each major human CYPs towards the FA metabolism. Incubations of FA with human liver microsomes (HLM) displayed NADPH- and UDPGA-dependent metabolism with multiple CYP and UGT isoforms involved. CYPs and UGTs contributed equally to the metabolism of FA in HLM. Although CYP1A2 and CYP3A4 appeared to be the major contributors in the CYP-mediated clearance, their contributions to the overall clearance are still minor (< 25%). As a constitute of many food and herbs, FA poses low drug-drug interaction risk when co-administrated with other herbs or conventional medicines because multiple phase I and phase II enzymes are involved in its metabolism.
Subject(s)
Humans , Coumaric Acids , Chemistry , Metabolism , Cytochrome P-450 Enzyme System , Chemistry , Metabolism , Drugs, Chinese Herbal , Metabolism , Glucuronosyltransferase , Chemistry , Metabolism , Kinetics , Medicine, Chinese Traditional , Microsomes, Liver , ChemistryABSTRACT
Isochlorogenic acid A (ICQA), which has anti-inflammatory, hepatoprotective, and antiviral properties, is commonly presented in fruits, vegetables, coffee, plant-based food products, and herbal medicines. These herbal medicines are usually used in combination with other medicines in the clinic. However, little is known about the regulatory effects of ICQA on drug-metabolizing enzymes and the herb-drug interactions. In the present study, we evaluated the inhibitory potentials of ICQA on CYP1A2, CYP2C9, CYP2C19, CYP3A4, CYP2D6, and CYP2E1 in vitro based on a cocktail approach. The P450 and UGT activities in mice treated with ICQA for a prolonged period were also determined. Our results demonstrated that ICQA exhibited a weak inhibitory effect on CYP2C9 in human liver microsomes with IC being 57.25 μmol·L and Ki being 26.77 μmol·L. In addition, ICQA inhibited UGT1A6 activity by 25%, in the mice treated with ICQA (i.p.) at 30 mg·kg for 14 d, compared with the control group. Moreover, ICQA showed no mechanism-based inhibition on CYP2C9 or UGT1A6. In conclusion, our results further confirm a safe use of ICQA in clinical practice.
Subject(s)
Animals , Humans , Mice , Chlorogenic Acid , Chemistry , Cytochrome P-450 Enzyme Inhibitors , Chemistry , Cytochrome P-450 Enzyme System , Chemistry , Metabolism , Glucuronosyltransferase , Chemistry , Metabolism , Kinetics , Mice, Inbred C57BL , Microsomes, Liver , ChemistryABSTRACT
OBJECTIVES: Banha-sasim-tang (BST), which consists of seven different herbs, is one of the most popular herbal formulae for treating gastrointestinal disorders in Eastern Asia. The commonly used herbal medicine is often co-administered with other therapeutic drugs, which raises the possibility of herb–drug interactions and may modify the clinical safety profile of therapeutic drugs. METHODS: We investigated the potential herb–drug interactions between BST extract and midazolam (MDZ) in mice. The area under the plasma concentration-time curve (AUC) of MDZ and 1ʹ-hydroxymidazolam (1ʹ-OH-MDZ) was evaluated for both oral and intraperitoneal administration of MDZ, following oral administration of BST (0.5 and 1 g/kg). RESULTS: It was found that the AUC of MDZ and 1ʹ-OH-MDZ was lower in case of oral administration of MDZ. Administration of BST extract was not associated with hepatic cytochrome P450 activity. BST extract induced a strong reduction in pH and it has been reported that oral mucosal absorption of MDZ is lower at low pH. The decreased absorption rate of MDZ might be caused by the ingredients of BST and may not be related to other factors such as increased excretion of MDZ by P-glycoprotein. CONCLUSIONS: The altered pharmacokinetics of midazolam caused by co-administration with BST in vivo could be attributed to a decrease in pH and subsequent reduction of MDZ absorption rate.
Subject(s)
Animals , Mice , Absorption , Administration, Oral , Area Under Curve , Cytochrome P-450 Enzyme System , Asia, Eastern , Herb-Drug Interactions , Herbal Medicine , Hydrogen-Ion Concentration , Midazolam , Oral Mucosal Absorption , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Pharmacokinetics , Plasma , StomachABSTRACT
Background: The non-medical self-administration of memory enhancing drugs is a common practice. Present study was designed to evaluate interactions of two such herbal drugs Memory Plus (MP) and Mentat, with other central nervous system (CNS) active drugs. Methods: Two activities - pentobarbitone sleeping time (PST) and maximal electroshock seizures (MES) were performed using adult albino mice weighing 25-30 g to observe the interactions of the herbal drugs with diazepam and phenytoin sodium, respectively. For each activity, animals were divided into seven groups of six mice each. Group I was a control group receiving 0.2 ml of 1% Tween 80 i.p/0.2 ml saline p.o, Group II, III and IV acute treatment groups; received single dose of herbal (2 mg/kg i.p MP or 200 mg/kg p.o Mentat) CNS-active drugs alone in subeffective doses group II - diazepam 5 mg/kg i.p, Group III PS 15 mg/kg i.p and Group IV - MP/Mentat+diazepam or PS, respectively. Groups V, VI, and VII were subchronic treatment groups, received drugs once daily for 8 days same as acute treatment groups. Sleeping time was measured as the interval between the loss and recovery of righting refl ex and anticonvulsant activity by giving supra maximal shock via ear electrodes using a techno electro convulsiometer. Results: Both MP and Mentat showed potentiation of effect of diazepam and PS in subchronic treatment groups by signifi cantly prolonging PST (p<0.05) and by showing signifi cant percentage protection in MES method (p<0.05) compared to control group. Conclusion: Subchronic administration of MP and Mentat shows significant interaction with diazepam and PS. Further human studies are warranted to confi rm these fi ndings.
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Aim To evaluate the inhibitive and induc-tive effects of Polygonum capitatum water extract on main cytochrome P450 isoforms in human and liver mi-crosomes of mouse in vitro for predicting the herb-drug interactions in clinical application. Methods The in vitro inhibitory effect was evaluated by incubating Po-lygonum capitatum water extract with the probe sub-strates of main phase I metabolic enzymes in human liver microsomes, including CYP1A2, CYP2E1, CYP2C9,CYP2C19 and CYP3A4. Mice were adminis-tered with Polygonum capitatum water extract at dosage of 0 . 58 g · kg-1 and 1 . 16 g · kg-1 by gastric lavage for successive 7 days and 14 days, then the cocktail-LC-MS/MS method was applied to assess the inductive effect of main CYP450 isoforms in mouse liver micro-somes. Results The IC50 values of Polygonum capita-tum water extract on main CYP450 isoforms in human liver microsomes were from 849 . 6 mg · L-1 to 2 287 mg·L-1 . Compared with the blank control group, the activites of CYP2C9 and CYP3A4 in 1. 16 g·kg-1 7 d group were about 49 . 9 % and 21. 1 % higher ( P <0. 01, P < 0. 05 ) respectively, the activities of CYP2C9 and CYP3A4 in 0. 58 g·kg-1 7 d group were 27. 6 % and 15. 5 % higher ( P <0. 01 , P <0. 05 ) respectively, the activities of CYP2C9 and CYP3A4 in 1. 16 g·kg-1 14 d group were 67. 5 % and 32. 1 %higher (P<0. 01) respectively, while the activities of CYP1 A2 , CYP2 E1 and CYP2 C19 were not increased significantly in Polygonum capitatum treatment group. Conclusions Polygonum capitatum water extract do not show the inhibitory effect on main CYP450 in hu-man liver microsomes. There is induction on CYP2C9 and CYP3 A4 in mouse liver microsomes by Polygonum capitatum water extract.
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Background: As herbal therapies are increasingly being used around the world because they are perceived to be free of side effects, it is important that prescribers should be made aware of their possible harm or herb-drug interactions. In this context present study was undertaken among dental students to assess their knowledge and attitude towards the use of herbal products as medicines. Methods: A detailed questionnaire having both open and close-ended questions to assess students’ perception, awareness and usage of herbal medication was given to 90 second year students in a teaching dental hospital. Data was expressed as counts and percentages. Results: A total response rate of 93.3% was observed. 60.77% of respondents had used herbal medication for various ailments. Highest frequency of the use was recorded for ginger (37.5%) followed by neem (16.66%), turmeric (15%) and tulsi (13.33%). Elders at home (86%) was cited the most common source of herbal product information. Students were familiar with the use of clove, aloe vera, turmeric and neem but St. John's wort and Gingko biloba are ones that were generally not known to them. 67.64% indicated unawareness about safety concerns and herb-drug interactions. Most (68.65%) agreed that they did not tell their physician about taking herbal products. 58.73% preferred herbal products over allopathic medicine. Conclusions: There is a need to impart knowledge to the students about the usage of herbal products as these are frequently used to treat various health problems. Students should be sensitized about their safety concerns and potential drug interactions.
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Synergism between water, ethanol and ethyl acetate extract of Melissa officinalis and five commonly used antibiotics (streptomycin, chloramphenicol, tetracycline, amoxicillin, rifamycine) were investigated by disc diffusion method in relation to antibiotic-susceptible and antibiotic resistant human-pathogenic bacteria. The total phenol content in the extracts were determined by Folin-Ciocalteau`s method while the flavonoid concentration by aluminium chloride method. The extracts, at least with one antibiotic, showed synergistic interaction. Depending on the species of bacteria, the zones of inhibition in extract/antibiotic plates were in the range of 0.5 – 11.5 mm wider than in controls. The certain extract/antibiotic combinations exhibited significant results against antibiotic resistant bacteria (the inhibition zones were 7- 11mm wider than in controls). The ethanol and ethyl acetate extracts showed better synergistic capacity than water extract. The least susceptible bacteria to extract/antibiotic combinations were Escherichia coli, Pseudomonas aeruginosa and Proteus mirabilis. The highest amount of total phenols was measured in water extract while the highest amount of flavonoids had ethyl acetate extract.
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Background & objectives: Currently, herbal preparations are clinically used as functional food, food supplements or as add on therapy, which affects the bioavailability and also the net therapeutic potential of co-administered allopathic drugs. Therefore, it is important to assess the interaction among these two classes of drugs. Here we studied the interaction between orally-administered ethanolic extract of leaves of Vitex negundo Linn. (Verbenaceae) (VN extract) and paracetamol in albino rats. Method: Solvent free dried extract of VN leaves was orally given to experimental rats in different doses (62.5-1000 mg/kg/b.wt.), daily for six consecutive days. On days 3 and 6, paracetamol (100 mg/kg/b.wt.) was orally administered to these extract treated rats and control rats (drug vector). At various time intervals (5 min - 120 min), blood was collected from each animal and paracetamol concentration was determined in plasma by using HPLC with UV detector at 249 nm. Various pharmacokinetic parameters were calculated by non compartmental model. Results: A significant decline in plasma concentration of paracetamol with time-gap was recorded with the increasing dose of VN extract, without affecting its Tmax (maximum time to achieve peak plasma concentration). There was a significant decrease in the extent of absorption and decline in intensity of therapeutic response (as evidenced by reduced AUC value and decline in Cmax). Further, compared to control, the relative bioavailability of paracetamol, in presence of VN extract, decreased significantly. Interpretation & conclusions: VN extract or its ayurvedic formulation if co-administered with allopathic drug like paracetamol, the dose of allopathic drug needs to be adjusted in order to achieve desired therapeutic response of paracetamol.