Evaluation of the effect of quercetin treatment on CYP2C9 enzyme activity of diclofenac in healthy human volunteers

The purpose of present study was to evaluate the effect of quercetin on pharmacokinetics of diclofenac sodium (DIC) in healthy volunteers. The open‐label, 2 period, sequential study was conducted in 12 healthy volunteers. DIC 100 mg was administered during control and after quercetin phases. Quercetin 500 mg was administered twice daily for 10 days during quercetin phase. Treatment with quercetin significantly enhanced maximum plasma concentration (C_max)_, area under the curve (AUC_0‐∞), and half life, while significantly decreased elimination rate constant (k_el) and apparent oral clearance (CL/F) of DIC compared with control. On the other hand, C_max and AUC_0‐∞ of 4‐hydroxydiclofenac (4‐OHDIC) were decreased after quercetin treatment. In addition, geometric mean ratios and 90% confidence intervals for C_max and AUC_0‐∞ of DIC and 4‐OHDIC were both out of the no‐effect limits of 0.80–1.25, which indicates a significant pharmacokinetic interaction between quercetin and DIC. Furthermore, quercetin treatment significantly decreased metabolic ratios of C_max and AUC_0‐∞ suggesting that reduced formation of DIC to 4‐OHDIC. The results suggest that quercetin might have inhibited CYP2C9‐mediated metabolism of DIC. Accordingly, caution should be taken when quercetin is used in combination with therapeutic drugs metabolized by CYP2C9, and dose adjustment of CYP2C9 substrates may be necessary.     

Effect of berberine on the pharmacokinetics of substrates of CYP3A and P‐gp

The in vivo effects of berberine (BBR), the widely used bioactive herbal ingredient from many traditional Chinese medicinal herbs, on the pharmacokinetics of carbamazepine (CBZ, a substrate of CYP3A) and its metabolite carbamazepine 10,11‐epoxide (ECBZ), digoxin (DIG, a substrate of P‐gp) and cyclosporine A (CsA, a dual substrate of CYP3A and P‐gp) were evaluated in rats. After a 2‐week pretreatment with BBR, the pharmacokinetic parameters of i.g. administered CBZ and ECBZ were not significantly altered. The pharmacokinetics of i.v. administered DIG was not modified by single and 2‐week pretreatments with BBR, but a dose‐dependent increase in AUC and C_max was observed in the i.g. administered DIG parameters in rats. The AUCs of DIG with BBR (30 mg/kg, 100 mg/kg) were 133%, 170% (single) and 123%, 169% (2‐week) of control, respectively. The AUC and C_max of i.g. administered CsA with a 2‐week pretreatment with BBR increased by 62% and 43% (BBR 30 mg/kg, p < 0.05), 96% and 60% (BBR 100 mg/kg, p < 0.01), compared with the control. In conclusion, berberine produced a dose‐dependent increased bioavailability of digoxin and cyclosporine A by inhibition of intestinal P‐gp. No significant changes in CYP3A activity by berberine were observed. Copyright © 2009 John Wiley & Sons, Ltd.     

Reduced bioavailability of tamoxifen and its metabolite 4-hydroxytamoxifen after oral administration with biochanin A (an isoflavone) in rats

The aim of this study was to investigate the effect of biochanin A (BCA) on the pharmacokinetics of tamoxifen, a substrate of P‐glycoprotein (P‐gp) and cytochrome 3A (CYP3A), in female rats. The tamoxifen was administered orally (10 mg/kg) without or with oral BCA (100 mg/kg) in female rats. As BCA is an inhibitor of CYP 3A and P‐gp it was expected to increase the bioavailability of tamoxifen, a known substrate of CYP3A4/Pgp. Surprisingly, compared with the control group (treated with tamoxifen alone), BCA pretreated animals showed significantly (p < 0.05) decreased area under the plasma concentration–time curve from time zero to time infinity (AUC_0‐∞) and peak tamoxifen concentrations (C_max). Consequently, the relative bioavailability (RB%) of tamoxifen co‐administered with BCA was remarkably decreased compared with the control group. The AUC_0‐∞ and C_max of 4‐hydroxytamoxifen in BCA pretreated rats were also significantly (p < 0.05) lower than those from the control group. However, there were no apparent changes in the metabolite ratio (MR; AUC_0‐∞ of 4‐hydroxytamoxifen to tamoxifen) by co‐administration of BCA. If the results of this study are further confirmed by clinical trials, tamoxifen dosages should be adjusted to avoid potential drug interaction when tamoxifen is used clinically in combination with BCA and BCA‐containing dietary supplements. Copyright © 2011 John Wiley & Sons, Ltd.     

Evaluation of First‐Pass Cytochrome P4503A (CYP3A) and P‐glycoprotein Activities Using Felodipine and Hesperetin in Combination in Wistar Rats and Everted Rat Gut Sacs in Vitro

The effects of hesperetin on the pharmacokinetics and the role of P‐glycoprotein (P‐gp) in the transport of felodipine were investigated in rats and in vitro. Felodipine was administered orally (10 mg/kg) without or with hesperetin (25, 50 and 100 mg/kg) to rats for 15 consecutive days. Blood samples were collected at different time intervals on 1^st day in single dose pharmacokinetic study (SDS) and on 15^th day in multiple dose pharmacokinetic study (MDS). The area under the plasma concentration–time curve (AUC_0–∞) and the peak plasma concentration (C_max) of felodipine were dose‐dependently increased in SDS and MDS with hesperetin compared to control ( p < 0.001). The half‐life (t_1/2) and mean residence time was longer than the control group in both studies. The role of P‐gp determined using everted rat gut sacs in vitro by incubating felodipine with or without hesperetin and verapamil (typical P‐gp and CYP3A4 inhibitor). The in vitro experiments revealed that the verapamil and hesperetin increased the intestinal absorption of felodipine (p < 0.01). Concurrent use of hesperetin dramatically altered the pharmacokinetics of felodipine leading to an increase in systemic exposure. The likely mechanism is inhibition of CYP3A4‐mediated first‐pass metabolism and P‐gp in the intestine and the liver. Copyright © 2013 John Wiley & Sons, Ltd.     

Effects of Panax notoginseng saponins on the activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in rats in vivo

The aim of this study was to assess the influence of the Panax notoginseng saponins (PNS) on the activities of the drug‐metabolizing enzymes cytochrome P450 (CYP450) 1A2, 2 C9, 2D6 and 3A4 in rats. The activities of CYP1A2, 2 C9, 2D6 and 3A4 were measured using specific probe drugs. After pretreatment for 1 week with PNS or physiological saline (control group), probe drugs caffeine (10 mg/kg; CYP1A2 activity), tolbutamide (15 mg/kg; CYP2C9 activity), metoprolol (20 mg/kg; CYP2D6 activity) and dapsone (10 mg/kg; CYP3A4 activity) were administered to rats by intraperitoneal injection. The blood was then collected at different times for ultra performance liquid chromatography/tandem mass spectrometry (UPLC‐MS/MS) analysis. The data showed that PNS exhibited an induction effect on CYP1A2 by decreasing caffeine C_max (36.3%, p < 0.01) and AUC_0‐∞ (22.77%, p < 0.05) and increasing CL/F (27.03%, p < 0.05) compared with those of the control group. Western blot analysis was used to detect the effect of PNS on the protein level of CYP1A2, and the results showed that PNS could upregulate the protein expression of CYP1A2. However, no significant changes in CYP2C9, 2D6 or 3A4 activities were observed. In conclusion, the results indicate that PNS could induce CYP1A2, which may affect the disposition of medicines primarily dependent on the CYP1A2 pathway. Our work may be the basis of related herb–drug interactions in the clinic. Copyright © 2011 John Wiley & Sons, Ltd.     

Effects of Silymarin,Glycyrrhizin, and Oxymatrine on the Pharmacokinetics of Ribavirin and Its Major Metabolite in Rats

The herb‐derived compounds silymarin, glycyrrhizin, and oxymatrine are widely used to treat chronic hepatitis C virus infections in China. They are often prescribed in combination with ribavirin, which has a narrow therapeutic index. We investigated the influence of these compounds on ribavirin pharmacokinetics following concurrent administration at the human dose in rats. Pharmacokinetic parameters were determined in rats following oral (PO) administration of ribavirin (30 mg/kg) with or without silymarin (40 mg/kg, PO), glycyrrhizin (15 mg/kg, intraperitoneal [IP]), or oxymatrine (60 mg/kg, PO). Compared with the animals in ribavirin group, silymarin significantly decreased the area under the plasma concentration‐time curve (AUC_0–t) and the peak plasma concentration (C_max) of ribavirin and ribavirin base by 31.2–44.5% and 48.9–50.0%, respectively. Glycyrrhizin significantly decreased the C_max and AUC_0–t of both ribavirin and its metabolite by 35.3–37.6% and 38.6–39.8%, respectively. However, silymarin or glycyrrhizin did not change the ribavirin metabolite/parent ratios of the AUC and C_max. Oxymatrine did not induce significant changes in ribavirin concentration, but it significantly decreased the C_max (26.6%) and AUC (21.8%) of the metabolite. This study indicates that the therapeutic efficacy of ribavirin may be compromised by the concurrent administration of herbal medicines/dietary supplements containing silymarin, glycyrrhizin, or oxymatrine. Copyright © 2016 John Wiley & Sons, Ltd.     

Impact of Tetrahydropalmatine on the Pharmacokinetics of Probe Drugs for CYP1A2, 2D6 and 3A Isoenzymes in Beagle Dogs

Tetrahydropalmatine (Tet) exhibit multiple pharmacological activities and is used frequently by clinical practitioners. In this study, we evaluate the in vivo effects of single and repeated oral Tet administrations on CYP1A2, 2D6 and 3A activities in six beagle dogs in a randomized, controlled, open‐label, crossover study. A cocktail approach, with dosages of the probe drugs caffeine (3.0 mg/kg), metoprolol (2.33 mg/kg) and midazolam (0.45 mg/kg), was used to measure cytochrome P450 (CYP) metabolic activities. The cocktail was administered orally as a single dose (12 mg/kg) 1 day prior to and 4 days after repeated oral Tet administrations (12 mg/kg three times daily). The probe drugs and their metabolites in plasma were quantified simultaneously by a validated HPLC technique, and non‐compartmental parameters were used to evaluate metabolic variables for assessment of CYP inhibition or induction. Tet had no or minor impact on the pharmacokinetics and metabolism of the probe drugs caffeine and metoprolol, CYP1A2 and CYP2D6 substrates, respectively. However, Tet increased AUC_{0–24 h} and decreased AUC_{ratio(0–24 h)} (1‐hydroxymidazolam/midazolam ratio) for midazolam statistically significant, both in single or multiple dosing of Tet, with up to 39 or 57% increase for AUC_{0–24 h} and 29% or 22 decrease for AUC_{ratio(0–24 h),} respectively, in line with previous in vitro findings for its CYP3A4 inhibition. The extensive use of Tet and herbal medicines containing Tet makes Tet a candidate for further evaluation of CYP3A‐mediated herb–drug interactions. Copyright © 2016 John Wiley & Sons, Ltd.     

Scutellarin inhibits cytochrome P450 isoenzyme 1A2 (CYP1A2) in rats

Scutellarin is the most important flavone glycoside in the herbal drug Erigeron breviscapus (Vant.) Hand.‐Mazz. It is used frequently in the clinic to treat ischemic vascular diseases in China. However, the direct relationship between scutellarin and cytochrome P450 (CYP450) is unclear. The present study investigated the in vitro and in vivo effects of scutellarin on cytochrome P450 1A2 (CYP 1A2) metabolism. According to in vitro experiments, scutellarin (10–250 µ m ) decreased the formation of 4‐acetamidophenol in a concentration‐dependent manner, with an IC₅₀ value of 108.20 ± 0.657 µ m . Furthermore, scutellarin exhibited a weak mixed‐type inhibition against the activity of CYP1A2 in rat liver microsomes, with a K_i value of 95.2 µ m . Whereas in whole animal studies, scutellarin treatment for 7 days (at 5, 15, 30 mg/kg, i.p.) decreased the clearance (CL), and increased the T_1/2 (at 15, 30 mg/kg, i.p.), it did not affect the V_d of phenacetin. Scutellarin treatment (at 5, 15, 30 mg/kg, i.p.) increased the AUC_0‐∞ by 14.3%, 67.3% and 159.2%, respectively. Scutellarin at 30 mg/kg also weakly inhibited CYP1A2 activity, in accordance with our in vitro study. Thus, the results indicate that CYP1A2 is inhibited directly, but weakly, by scutellarin in vivo, and provide useful information on the safe and effective use of scutellarin in clinical practice. Copyright © 2012 John Wiley & Sons, Ltd.     

Cocktail探针药物法评价辣椒素对大鼠CYP1A2,2C11和3A作用的研究

 目的 用“cocktail”探针药物法研究单次或多次口服辣椒素对大鼠肝药酶CYP1A2、CYP2C11和CYP3A的影响。方法 将雄性SD大鼠随机分组,给予辣椒素25 mg·kg^-1,分别灌胃1, 3, 7 d,以0.5%羧甲基纤维素钠作为空白对照组,每组8只,给药后于不同的时间点采集血样。用HPLC测定大鼠血浆中探针药物咖啡因、甲苯磺丁脲和氨苯砜的浓度,血药浓度-时间数据采用DAS2.1.1软件进行药动学分析。结果 与对照组相比,辣椒素灌胃7 d后,咖啡因的AUC_0-t、AUC_0-∞和ρ_max显著减小, CL/F显著增大;甲苯磺丁脲的AUC_0-t显著减小,ρ_max极显著减小;氨苯砜的AUC_0-t和AUC_0-∞极显著减小,CL/F和V/F极显著增大。结论 辣椒素灌胃7 d后对大鼠肝药酶CYP1A2、CYP2C11和CYP3A可能存在不同程度的诱导作用,其中对CYP3A的诱导作用较强。     

Fennel and Raspberry Leaf as Possible Inhibitors of Acetaminophen Oxidation

In addition to CYP2E1, several CYP isoenzymes, notably CYP1A2, 2D6, and 3A4, are suggested to contribute in acetaminophen oxidation and formation of the hepatotoxic metabolite N‐acetyl‐p‐benzoquinone imine (NAPQI). The in vitro CYP2E1 inhibitory potentials of fennel and raspberry leaf, herbs previously found to inhibit CYP1A2, 2D6, and 3A4 activities in vitro, were investigated. Extracts from commercially available herbal products were incubated with recombinant cDNA‐expressed human CYP2E1. A validated LC/MS/MS methodology was applied for determination of 6‐hydroxychlorzoxazone formation with disulfiram used as a positive inhibitory control. CYP2E1 IC₅₀ inhibition constants were found to be 23 ± 4 and 27 ± 5 µg/ml for fennel and raspberry leaf, respectively, constants significantly lower than those presented in the literature for other herbal extracts. Together with previous findings, the presented in vitro data for CYP2E1 inhibition suggest that fennel and raspberry leaf have a significant potential of inhibiting all the major metabolic pathways for acetaminophen oxidation and NAPQI formation. Both herbs should be further investigated for their in vivo ability of inhibiting acetaminophen oxidation and NAPQI formation. Copyright © 2014 John Wiley & Sons, Ltd.     

Effect of Ginkgo Biloba Extract on the Pharmacokinetics and Metabolism of Clopidogrel in Rats

Ginkgo biloba extract (GBE), a traditional herbal product used worldwide as both medicine and supplement, is often supplied with clopidogrel for the treatment of cerebrovascular diseases. The aim of the current study was to explore the effect of GBE on the metabolism and pharmacokinetics of clopidogrel. The in vitro study using rat liver microsomes revealed that GBE significantly induced the conversion of clopidogrel into its active metabolite. The effect of GBE on the pharmacokinetics of clopidogrel was also investigated in vivo. Compared to rats without GBE pretreatment, administration of 4 mg/kg, 20 mg/kg, and 100 mg/kg of GBE significantly decreased the C_max and the AUC_0–∞ of clopidogrel in a dose‐dependent manner. As expected, pretreatment of high dose GBE significantly increased the C_max and AUC_0–∞ of the clopidogrel active metabolite. However, no marked change was observed following medium and low dose of GBE, suggesting that the biotransformation of clopidogrel was altered differently by high dose of GBE. Our study suggested that the awareness of the potential herb–drug interactions between GBE and clopidogrel should be increased in clinical practice. Copyright © 2016 John Wiley & Sons, Ltd.     

泮托拉唑在不同CYP2C19基因型国人体内的药动学

 目的研究CYP2C19基因型对泮托拉唑中国健康志愿者体内药动学的影响。方法采用聚合酶链限制性片断长度多态性(PCR-RFLP)分析CYP2C19基因型。24名健康志愿者按照基因型划分的基因表型被随机分为3组(每组8名),纯合子强代谢型组(homEMs),杂合子强代谢型组(hetEMs),弱代谢型组(PMs)。受试者单剂量po 40mg泮托拉唑肠溶片后血药浓度的测定采用高效液相色谱法。结果HomEMs,hetEMs,PMs3组个体内的泮托拉唑的主要药动学参数如下:ρ_max为(2551.8±1035.2),(3316.63±1237.27)和(4256.04±573.47)μg·L^-1;t_max为(3.38±0.92),(3.25±1.54)和(3.50±0.96)h;t_1/2Ke为(1.82±1.71),(1.34±0.22)和(5.83±3.28)h;AUC_0～t为(5616.37±1878),(8132.22±3549.4)和(24882.71±7051.33)μg·h·L^-1;AUC_0～∞为(5699.5±1932.1),(8238.5±3513.3)和(32394.9±12428.3)μg·h·L^-1。HetEM组和PM组的受试者其泮托拉唑的ρ_max高于homEM组(P<0.01),PM组的t_1/2Ke要长于homEM组(P<0.01)。AUC_0～t和AUC_0～∞在PM组要分别高于homEM组和hetEM组(P<0.01),但在homEM组和hetEM组之间没有差异。结论泮托拉唑药动学在个体之间的差异与CYP2C19的基因型有关。     

临床治疗剂量喹硫平体内代谢机制研究

 目的探讨临床治疗剂量喹硫平体内代谢机制。方法19例病人均经历多剂量单独使用喹硫平和多剂量喹硫平与红霉素合用两个周期。同时,给予单剂量的咪达唑仑测定酶活性。在一定的时间间隔内采集血样,用HPLC-MS/ESI⁺测定喹硫平及其3个代谢产物浓度;用HPLC-UV测定咪达唑仑及其代谢产物浓度。结果喹硫平与红霉素联用后,CYP3A4活性显著下降;喹硫平的ρ^SS_max,AUC^SS_0-24和t_1/2显著增加,CL/F显著下降,AUC^SS_O-24和CL/F的改变量分别与CYP3A4活性改变量负和正相关;磺氧化喹硫平的ρ^{SS_max,AUCSS_0-24显著减少,t_1/2显著延长,t_1/2的改变量与CYP3A4活性改变量正相关;7-羟基喹硫平的ρSS_max和AUCSS_O-24没有显著性改变,t_1/2显著延长并与CYP3A4活性相关;7-羟基-氮去烷基-喹硫平的t_1/2没有显著性改变,ρSS_max和AUCSS_O-24显著下降,AUCSS_O-24的改变量与CYP3A4活性改变量正相关。结论喹硫平的磺氧化和氮去烷基化主要由CYP3A4催化,7-羟基化不是主要由CYP3A4催化,其中磺氧化是喹硫平的体内主要代谢途径。}     

Effects of Vernonia cinerea Compounds on Drug‐metabolizing Cytochrome P450s in Human Liver Microsomes

Vernonia cinerea has been widely used in traditional medicines for various diseases and shown to aid in smoking abstinence and has anticancer properties. V. cinerea bioactive compounds, including flavonoids and hirsutinolide‐type sesquiterpene lactones, have shown an inhibition effect on the nicotine‐metabolizing cytochrome P450 2A6 (CYP2A6) enzyme and hirsutinolides reported suppressing cancer growth. In this study, V. cinerea ethanol extract and its bioactive compounds, including four flavonoids and four hirsutinolides, were investigated for an inhibitory effect on human liver microsomal CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 using cocktail inhibition assays combined with LC‐MS/MS analysis. Among tested flavonoids, chrysoeriol was more potent in inhibition on CYP2A6 and CYP1A2 than other liver CYPs, with better binding efficiency toward CYP2A6 than CYP1A2 (K_i values in competitive mode of 1.93 ± 0.05 versus 3.39 ± 0.21 μM, respectively). Hirsutinolides were prominent inhibitors of CYP2A6 and CYP2D6, with IC₅₀ values of 12–23 and 15–41 μM, respectively. These hirsutinolides demonstrated time‐dependent inhibition, an indication of mechanism‐based inactivation, toward CYP2A6. Quantitative prediction of microsomal metabolism of these flavonoids and hirsutinolides, including half‐lives and hepatic clearance rate, was examined. These findings may have implications for further in vivo studies of V. cinerea. Copyright © 2017 John Wiley & Sons, Ltd.     

Protective Effects of a Purified Saponin Mixture from Astragalus corniculatus Bieb., in vivo Hepatotoxicity Models

In this study, the in vivo effects of a purified saponin mixture (PSM), obtained from Astragalus corniculatus Bieb., were investigated using two in vivo hepatotoxicity models based on liver damage caused by paracetamol (PC) and carbon tetrachloride (CCl₄). The effects of PSM were compared with silymarin. Male Wistar rats were challenged orally with 20% CCl₄ or PC (2 g/kg) four days after being pre‐treated with PSM (100 mg/kg) or silymarin (200 mg/kg). A significant decrease of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase (LDH) activities and glutathione (GSH) levels and an increase of malondialdehyde (MDA) quantity was observed after CCl₄ and PC administration alone. PSM pre‐treatment decreased serum transaminases and LDH activities and MDA levels and increased the levels of cell protector GSH. Biotransformation phase I enzymes were also assessed in both models. In the CCl₄ hepatotoxicity model, pre‐treatment with PSM or silymarin resulted in significantly increased activities of ethylmorphine‐N‐demethylase and aniline 4‐hydroxylase activity and cytochrome P450, compared to the CCl₄ only group. Neither silymarin nor PSM influenced PC biotransformation. Our results suggest that PSM, obtained from A. corniculatus, Bieb. showed in vivo hepatoprotective and antioxidant activities against CCl₄ and PC‐induced liver damage comparable to that of silymarin. Copyright © 2012 John Wiley & Sons, Ltd.     

Effect of Wuzhi Tablet (Schisandra sphenanthera extract) on the Pharmacokinetics of Cyclosporin A in Rats

In our previous reports, Wuzhi tablet (an herbal preparation of ethanol extract of Wuweizi (Schisandra sphenanthera)) can significantly increase the blood concentration of tacrolimus and paclitaxel in rats by inhibiting the CYP3A‐mediated metabolism and the P‐gp‐mediated efflux. Cyclosporin A (CsA), a well‐known immunosuppressant agent, is also a substrate of CYP3A and P‐gp. Therefore, this study aimed to investigate whether and how WZ affects pharmacokinetics of CsA in rats. The AUC_0–48h and C_max of CsA were increased by 40.1% and 13.1%, respectively, with a single oral co‐administration of WZ and high dose of CsA (37.8 mg/kg). Interestingly, after a single oral co‐administration of WZ and low dose of CsA (1.89 mg/kg), the AUC_{0–36 h} and C_max of CsA were dramatically increased by 293.1% (from 1103.2 ± 293.0 to 4336.5 ± 1728.3 ng.h/mL; p < 0.05) and 84.1% (from 208.5 ± 67.9 to 383.1 ± 92.5 ng/mL; p < 0.05), respectively. The CL/F was decreased from 1.7 L/h/kg to 0.5 L/h/kg. Thus, the effect of WZ on high dose of CsA was not significant, but pharmacokinetic parameters of CsA at low dose were significantly influenced by co‐administration of WZ. The herb–drug interaction should be taken into consideration at this situation. Copyright © 2012 John Wiley & Sons, Ltd.     

Dose–Response Effects of p‐Synephrine on Fat Oxidation Rate During Exercise of Increasing Intensity

The aim of this investigation was to determine the effects different doses of p‐synephrine on maximal fat oxidation during exercise. Seventeen healthy subjects volunteered to participate in a double‐blind and randomised experimental design composed of four identical experimental trials. On four trials separated by 72 h, participants ingested a placebo or 1, 2 or 3 mg/kg of p‐synephrine. After resting for 60 min to allow substance absorption, participants performed an exercise test of increasing intensity on a cycle ergometer while gas exchange was measured continuously. None of the doses of p‐synephrine affected energy expenditure or heart rates during the test. The highest rate of fat oxidation with the placebo (0.35 ± 0.05 g/min) was reached at 38.0 ± 1.9% of VO_2max. The ingestion of 1 mg/kg increased maximal fat oxidation to 0.47 ± 0.11 g/min (p = 0.01) but did not change the intensity at which it was obtained (42.0 ± 9.4% of VO_2max). The ingestion of 2 and 3 mg/kg of p‐synephrine increased maximal fat oxidation to 0.55 ± 0.14 g/min (p < 0.01), although only 3 mg/kg slightly changed the intensity at which it was obtained (43.0 ± 9.5% of VO_2max, p < 0.01). In conclusion, although all p‐synephrine increased the maximal rate of fat oxidation during exercise, the highest effects were found with 2 and 3 mg/kg. Copyright © 2017 John Wiley & Sons, Ltd.     

Hypericum perforatum Reduces Paracetamol‐Induced Hepatotoxicity and Lethality in Mice by Modulating Inflammation and Oxidative Stress

Hypericum perforatum is a medicinal plant with anti‐inflammatory and antioxidant properties, which is commercially available for therapeutic use in Brazil. Herein the effect of H. perforatum extract on paracetamol (acetaminophen)‐induced hepatotoxicity, lethality, inflammation, and oxidative stress in male swiss mice were investigated. HPLC analysis demonstrated the presence of rutin, quercetin, hypericin, pseudohypericin, and hyperforin in H. perforatum extract. Paracetamol (0.15–3.0 g/kg, p.o.) induced dose‐dependent mortality. The sub‐maximal lethal dose of paracetamol (1.5 g/kg, p.o.) was chosen for the experiments in the study. H. perforatum (30–300 mg/kg, i.p.) dose‐dependently reduced paracetamol‐induced lethality. Paracetamol‐induced increase in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations, and hepatic myeloperoxidase activity, IL‐1β, TNF‐α, and IFN‐γ concentrations as well as decreased reduced glutathione (GSH) concentrations and capacity to reduce 2,2′‐azinobis‐(3‐ethylbenzothiazoline‐6‐sulfonate radical cation; ABTS˙⁺) were inhibited by H. perforatum (300 mg/kg, i.p.) treatment. Therefore, H. perforatum protects mice against paracetamol‐induced lethality and liver damage. This effect seems to be related to the reduction of paracetamol‐induced cytokine production, neutrophil recruitment, and oxidative stress. Copyright © 2015 John Wiley & Sons, Ltd.     

Chemoprotective effects of Ulva lactuca (green seaweed) aqueous‐ethanolic extract against subchronic exposure to benzo(a)pyrene by CYP1A1 inhibition in mice

The protective effect of the supplementation with an aqueous‐ethanolic extract obtained from Ulva lactuca (Delile) green seaweed on benzo[a] pyrene‐induced damage in mice was evaluated. Animals were treated with oral doses of U. lactuca extract (100 and 400 mg/kg) for 9 weeks. They were exposed to 50 mg/kg of oral doses of benzo(a)pyrene starting from the second week and up to the fifth week. Groups treated with benzo(a)pyrene only (second to fifth weeks), sunflower oil (vehicle, 9 weeks), or U. lactuca extract (100 and 400 mg/kg, 9 weeks) were also included in the study. The treatment with 400 mg/kg of the extract ameliorated the oxidative damage, decreased IL‐1β and TNF‐α levels, and favorably regulated the antioxidant defenses compared with benzo(a)pyrene‐exposed group. The benzo(a)pyrene‐induced DNA damage was also reduced, as it was evidenced by the lower micronucleus formation in U. lactuca extract‐supplemented animals. The extract protected the hepatic tissue, and it reduced the liver activity/expression of CYP1A1. These results altogether suggested a chemoprotective effect of U. lactuca extract against benzo(a)pyrene‐induced‐toxicity in mice, probably associated with an inhibitory effect of carcinogen bioactivation.     

Effects of ephedra water decoction and cough tablets containing ephedra and liquorice on CYP1A2 and the pharmacokinetics of theophylline in rats

Ephedra water decoction (EWD) and cough tablets containing ephedra and liquorice (maxing cough tablets, MXCT) have been used widely in the treatment of asthma. In the clinic, EWD and MXCT may be prescribed with theophylline, one of the most popular antiasthmatic drugs and a typical substrate of cytochrome P450 (CYP) 1A2. So in the present study the potential effects of EWD and MXCT on CYP1A2 activity and the pharmacokinetics of theophylline in rats were evaluated. In the in vivo CYP1A2 activity research, the rats were given oral caffeine (10 mg/kg) after a 14 day pretreatment with EWD (18 g/kg) and MXCT (0.1, 0.2 or 0.4 g/kg). Then the CYP 1A2 activity was expressed by using the caffeine metabolic ratio (CMR). The results showed that the CMR increased markedly compared with the control groups. In the pharmacokinetics experiment, the rats were given oral theophylline (10 mg/kg) after a 14 day pretreatment with EWD (18 g/kg) and MXCT (0.2 g/kg). The results showed that the AUC_{0‐24 h} and C_max of theophylline were reduced markedly compared with the control groups. These results demonstrated that EWD or MXCT pretreatment obviously induced CYP1A2 activity, therefore, speeding up the metabolism of theophylline. The concomitant use of EWD or MXCT may decrease the effect of theophylline in rats. Copyright © 2011 John Wiley & Sons, Ltd.