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ABSTRACT: Capsaicin and dihydrocapsaicin, the two most abundant members of capsaicinoids in chili peppers, are widely used as food additives and for other purposes. In this study, we examined the inhibitory potentials of capsaicin and dihydrocapsaicin against CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5 activities in human liver microsomes. The effects of these two capsaicinoids on CYP450 enzymes were also evaluated in vivo in rats. The results demonstrated that capsaicin and dihydrocapsaicin moderately inhibited five isozymes (IC₅₀) values ranging from 4.4 to 61.8 μM), with the exception of CYP2E1 (IC₅₀ > 200 μM). Both capsaicinoids exhibited competitive, mixed, and noncompetitive inhibition on these isozymes (K (i) = 3.1 ± 0.5 - 78.6 ± 8.4 μM). Time-dependent inhibition of CYP3A4/5 by capsaicin was found. After multiple administrations of capsaicin and dihydrocapsaicin (1, 4, and 10 mg/kg) to rats, chlorzoxazone 6-hydroxylase activity and the expression of CYP2E1 were increased in liver microsomes. Our findings indicated that the possibility of food-drug interactions mediated by capsaicin and dihydrocapsaicin could not be excluded, and provided the useful information for evaluating the anticarcinogenic potentials of these two capsaicinoids.
Journal of Asian natural products research 04/2012; 14(4):382-95. · 0.61 Impact Factor
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ABSTRACT: Effects of constituents from Schisandra chinensis (Wuweizi) on six liver microsomal CYP450 isozymes (CYP1A2, CYP2C6, CYP2C11, CYP2D2, CYP2E1 and CYP3A1/2) were studied in rats in vivo and in vitro. The in vitro incubation was conducted using liver microsomes of rats after multiple dosing of alcoholic/water extract from Schisandra chinensis. A HPLC-MS method was applied to determine the metabolites formation of six CYP450s probe substrates (phenacetin-CYP1A2, dextromethorphan-CYP2D2, diclofenac sodium-CYP2C6, mephenytoin-CYP2C11, chlorzoxazone-CYP2E1 and midazolam-CYP3A1/2) in rat liver microsomal incubations. The activity of CYP450 isozymes were represented by the formation of metabolites. Alcoholic extract of Schisandra chinensis (28-120 microg x mL(-1)) showed significant inhibitory effect on six CYP450 isozymes to a certain extent in vitro. Multiple dosing of Schisandra chinensis alcoholic extract (1.5 g x kg(-1), qd x 7d) had significant induction on CYP2E1 and CYP3A1/2, inhibition on CYP2D2 and CYP2C11, and no effect on CYP2C6 and CYP1A2. Water extract of Schisandra chinensis (100-500 microg x mL(-1)) also exhibited inhibition on the activity of CYP450 isozymes in vitro, whereas multiple administrations (1.5 g x kg(-1), qd x 7d) had significant induction of CYP2E1 and inhibition on CYP2D2, no effect on CYP2C6, CYP3A1/2, CYP1A2 or CYP2C11. The results suggested that the constituents from Schisandra chinensis exhibited the inhibition and induction on six rat liver microsomal CYP450 isozymes to a certain extent in vivo and in vitro. The possibility of interaction between Schisandra chinensis and coadministrative drugs will be considered base on the levels and subtype of CYP450 involved in the drug metabolism.
Yao xue xue bao = Acta pharmaceutica Sinica 08/2011; 46(8):922-7.
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ABSTRACT: The pharmacokinetics, tissue distribution, and excretion of buagafuran (BF, 4-butyl-α-agarofuran), a promising antianxiety drug isolated from Gharu-wood (Aquilaria agallocha Roxb), were investigated in rats. BF plasma concentration was determined in rats after oral and intravenous doses by GC-TOF-MS. BF showed nonlinear pharmacokinetics after oral and intravenous administration of 4, 16, and 64 mg/kg. The AUC(0-∞) and C(max) did not increase proportionally with doses, indicating the saturation in absorption kinetics of BF in rats after oral dosage. BF absorption was extremely poor with an absolute bioavailability below 9.5%. After oral administration of (3)H-BF (4 mg/kg) to rats, radioactivity was well distributed to the tissues examined. The highest radioactivity was found in gastrointestinal tract, followed by liver and kidney. Radioactivity in brain, as a target organ, was about 20-40% of that in plasma at all time points. Total mean percent recovery of radioactive dose was about 80% in rats (51.2% in urine; 28.7% in feces). Bile elimination was also the major excretion route of BF, and 45.4% of the radioactive dose was recovered in bile.
Journal of Asian natural products research 03/2011; 13(3):205-14. · 0.61 Impact Factor
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ABSTRACT: Buagafuran (BF), derived from alpha-agarofuran, is a promising anti-anxiety drug in phase I clinical trials. The present study was undertaken to examine the regulation of BF on liver cytochrome P450 (CYP) isoforms in rats. After being administered (4, 16, and 64 mg/kg) by gavage for 7 continuous days, the activities of CYP isoforms were measured by the qualification of six metabolites from CYP probe substrates using LC-MS/MS analysis. The mRNA and protein levels of CYPs were detected by reverse transcription polymerase chain reaction and Western blotting assay, respectively. Using phenacetin and chlorzoxazone as probe drugs, the activities of CYP1A2 and CYP2E1 were monitored in vivo. The result indicated that BF significantly increased the activity and protein levels of CYP1A2 and CYP2E1, while the mRNA levels were elevated to a certain extent. CYP2C6 and CYP2C11 were also slightly induced by BF, but no effect on liver CYP3A was detected in rats. Treatment of BF orally resulted in the decreasing of AUC, MRT and increasing of CL/F of phenacetin as well as production of acetaminophen in rats. The similar pharmacokinetic changes were also observed when using chlorzoxazone as a probe drug. Collectively, BF has inducing potential of liver CYP1A2 and CYP2E1 and may influence the corresponding pharmacokinetics of other drugs.
Journal of Asian natural products research 05/2010; 12(5):371-81. · 0.61 Impact Factor
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ABSTRACT: The rat single-pass intestinal perfusion model was applied to study the effect of CYP3A and P-glycoprotein on the absorption of buagafuran in lumen of rats. Buagafuran concentrations in intestinal perfusate and blood in vena mesenterica collected at different time points after perfusion were determined by GC-MS. Permeability coefficient of buagafuran was calculated by the equation [P(lumen) = -(Q/2pirl)Ln(C(out)/C(in)) and P(blood) = (deltaM(B)/deltat)/(2pirl )]. The effects of troleandomycin (TAO, CYP3A inhibitor), cyclosporin A (CYP3A/p-glycoprotein inhibitor) on the absorption of buagafuran in lumen were observed. After rat single-pass intestinal perfusion, the cumulative amount of buagafuran in mesenteric vein of rat was 73.4, 82.9, and 98.3 pmol x cm(-2) and were increased 3.9, 4.6, and 5.6 fold by addition of inhibitor of P-gp (LSN335984), CYP3A (TAO) or P-gp and CYP3A (CsA), respectively. Moreover, the metabolized fraction of buagafuran was decreased by 12%, 11% and 21% with inhibitors. The results suggested that the poor bioavailability of buagafuran was mostly due to the interplay of P-gp and CYP3A on the absorption, transport and metabolism of buagafuran in intestine of rats.
Yao xue xue bao = Acta pharmaceutica Sinica 01/2010; 45(1):43-8.
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ABSTRACT: A simple, rapid and sensitive method was developed for determination of bicyclol, a new synthetic anti-hepatitis drug, in rat plasma from the mesenteric vein using a high-performance liquid chromatography system coupled to a positive ion electrospray-mass spectrometric analysis. Bicyclol and internal standard (biphenyldicarboxylate, DDB) were isolated from plasma by liquid-liquid extraction, then separated on a Zorbax SB-C(18) column (3.5 microm, 2.1 x 100 mm) with mobile phase of methanol-water (60:40, v/v) at a flow rate of 0.2 mL/min. Detection was performed on a Trap XCT mass spectrometer equipped with an electrospray ionization (ESI) source operated in selected ion monitoring mode. Positive ion ESI was used to form sodium adduct molecular ions at m/z 413 for bicyclol and m/z 441 for DDB, respectively. A linear detection response was obtained for bicyclol ranging from 3.3 to 333.3 ng/mL and the lower limit of quantitation was 3.3 ng/mL. The coefficients of variation for intra- and inter-day precisions were 1.1-7.7 and 2.0-6.6%, respectively. The percentage of absolute recovery of bicyclol was 85.3-94.6%. All analytes proved to be stable during all sample storage, preparation and analytic procedures. The method was successfully applied to determine the plasma concentration of bicyclol in mesenteric vein after intestinal perfusion.
Biomedical Chromatography 04/2009; 23(10):1059-63. · 1.97 Impact Factor
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ABSTRACT: This paper is aimed to study the metabolic kinetics of nicousamide in rat liver microsomes and cytosol and to identify the major metabolite and drug metabolizing enzymes involved in the metabolism of nicousamide in rat and human liver microsomes by selective inhibitors in vitro. The concentration of nicousamide was determined by HPLC-UV method. The metabolite of nicousamide in rat and human liver microsomes was isolated and identified by LC-MS/MS. The major metabolite of nicousamide in rat and human liver microsomes was identified to be 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-amino-7-hydroxy-8-methyl-coumarin (M1). The metabolite of nicousamide in rat plasma, urine, bile and liver was consistent with M1. The metabolism of nicousamide can be catalyzed by several reductases, including CYP450 reductases, cytochrome b5 reductases and CYP2C6 in rat liver microsomes, as well as xanthine oxidase and DT-diaphorase in rat liver cytosol.
Yao xue xue bao = Acta pharmaceutica Sinica 10/2008; 43(9):912-6.
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Lin Wang,
Xing-quan Zhang,
Hong-shan Chen,
Pei-zhen Tao,
Yan Li,
Yu Bai, Jin-ping Hu,
Tao Ma,
Zhen-tang Xing,
Zong-gen Peng,
Chun-mei Zhou,
Qi Gao,
Gang Liu
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ABSTRACT: An improved and practical synthesis of racemic 11-demethylcalanolide A [(+/-)-1] was developed. This improved process involved Pechmann reaction on phloroglucinol with ethyl butyrylacetate to give 5,7,-dihydroxy4-n-propylcoumarin (3). Poly phosphoric acid (PPA) catalyzed acylation of compound (3) with crotonic acid, then intramolecular cyclization was achieved simultaneously in one step to afford the key intermediate chromanone (4). A microwave assisted synthetic method preparing chromene (6) using chromenynation of chromanone (4) with 1, 1-diethoxy-methyl-2-butene was conducted. Luche reduction of chromene (6) using NaBH4 with CeCl3 x 7H2O preferably gave (+/-)-1. The overall yield of this four step synthesis of (+/-)-1 was around 32% increasing one fold more than that of the previous method. An in vitro investigation showed that (+/-)-1 exhibited inhibitory activities against both wild-type and drug-resistant HIV-1 in HIV-1 RT and cell culture assay, and significant synergistic effects in combination with AZT, T-20, and indinavir. Its LD50 of acute toxicity in mice by intragastric administration and by intraperitoneal injection were 735.65 mg kg(-1) and 525.10 mg x kg(-1), respectively. The Cmax and AUC(0-infinity) were 0.54 microg x mL(-1) and 1.08 (microg x mL(-1) x h, respectively. The dynamics study of the inhibition of mice sera on HIV-1 RT showed that mice treated with 100 mg x kg(-1 (+/-)-1 once intraperitoneally were similar to that of 5 mg x kg(-1) of known clinical effective anti-HIV-1 drug neverapine. The results suggested that further investigation of the anti-HIV candidate (+/-)-1 was warranted.
Yao xue xue bao = Acta pharmaceutica Sinica 08/2008; 43(7):707-18.
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ABSTRACT: A simple, rapid and sensitive method was developed for the simultaneous quantification of four active schisandra lignans (schisandrin, schisantherin A, deoxyshisandrin and gamma-schisandrin) from a traditional Chinese medicine Schisandra chinensis(Wuweizi) in rat plasma using a high-performance liquid chromatography system coupled to a positive ion electrospray mass spectrometric analysis. The plasma sample preparation was a simple deproteinization by the addition of three volumes of methanol followed by centrifugation. The analytes and internal standard (IS) bicyclol were separated on a Zorbax SB-C18 column (3.5 microm, 2.1 mm x 100 mm) with mobile phase of methanol/water (70:30, v/v) containing 0.1% formic acid at a flow rate of 0.2 mL/min with an operating temperature of 25 degrees C. Detection was performed on a Trap XCT mass spectrometer equipped with an electrospray ionization (ESI) source operated in selected ion monitoring (SIM) mode. Positive ion ESI was used to form sodium adduct molecular ions at m/z 455 for schisandrin, m/z 559 for schisantherin A, m/z 439 for deoxyshisandrin, m/z 423 for gamma-schisandrin, and m/z 413 for the internal standard bicyclol. Linear detection responses were obtained for the four test compounds ranging from 0.010 to 2.0 microg/mL and the lower limits of quantitation (LLOQs) for four lignans were 0.010 microg/mL. The intra- and inter-day precisions (R.S.D.%) were within 12.5% for all analytes, while the deviation of assay accuracies was within +/-13.0%. The average recoveries of analytes were greater than 80.0%. All analytes were proved to be stable during all sample storage, preparation and analytic procedures. The method was successfully applied to the pharmacokinetic study of the four lignans after oral administration of Schisandra chinensis extraction to rats.
Journal of Chromatography B 05/2008; 865(1-2):114-20. · 2.89 Impact Factor
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ABSTRACT: Berberine, an isoquinoline alkaloid isolated from several medicinal plants, has been reported to possess anti-bacterial, anti-inflammatory and antitumor properties. Although berberine also inhibits osteoclastogenesis and bone resorption, the molecular machinery for its inhibitory effects remains unknown. This study focused on the suppressive effects of berberine on receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL)-induced osteoclastogenesis and survival. Berberine inhibited RANKL-mediated osteoclast formation and survival while having no cytotoxic effects on bone marrow macrophages or osteoblastic cells. Berberine attenuated RANKL-induced activation of NF-kappaB through inhibiting phosphorylation at the activation loop of IkappaBalpha kinase beta, phosphorylation and degradation of IkappaBalpha, and NF-kappaB p65 nuclear translocation. RANKL-induced Akt phosphorylation was strongly inhibited by berberine; however, neither monocyte/macrophage-colony stimulating factor (M-CSF)-induced nor insulin-induced Akt activation was inhibited by the drug. Under M-CSF- and RANKL-deprived condition, berberine increased the active form of caspase-3 in osteoclasts. By contrast, berberine did not potentiate the activation of caspase-3 in M-CSF-deprived bone marrow macrophages. These findings indicate that berberine inhibits osteoclast formation and survival through suppression of NF-kappaB and Akt activation and that both pathways in the osteoclast lineage are highly sensitive to berberine treatment.
European Journal of Pharmacology 03/2008; 580(1-2):70-9. · 2.52 Impact Factor
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Hajime Yoshida,
Kuniaki Okamoto,
Tsutomu Iwamoto,
Eiko Sakai,
Kazuhiro Kanaoka, Jin-Ping Hu,
Mitsue Shibata,
Hitoshi Hotokezaka,
Kazuhisa Nishishita,
Akio Mizuno,
Yuzo Kato
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ABSTRACT: Pepstatin A is well known to be an inhibitor of aspartic proteinases such as pepsin, cathepsins D and E. Except for its role as a proteinase inhibitor, however, the pharmacological action of pepstatin A upon cells remain unclear. In this study, we found that pepstatin A suppressed receptor activator of NF-kappaB ligand (RANKL)-induced osteoclast differentiation. Pepstatin A suppressed the formation of multinuclear osteoclasts dose-dependently. This inhibition of the formation only affected osteoclast cells, i.e., not osteoblast-like cells. Furthermore, pepstatin A also suppressed differentiation from pre-osteoclast cells to mononuclear osteoclast cells dose-dependently. This inhibition seems to be independent of the activities of proteinases such as cathepsin D, because the formation of osteoclasts was not suppressed with the concentration that inhibited the activity of cathepsin D. Cell signaling analysis indicated that the phosphorylation of ERK was inhibited in pepstatin A-treated cells, while the phosphorylation of IkappaB and Akt showed almost no change. Furthermore, pepstatin A decreased the expression of nuclear factor of activated T cells c1 (NFATc1). These results suggest that pepstatin A suppresses the differentiation of osteoclasts through the blockade of ERK signaling and the inhibition of NFATc1 expression.
Journal of Biochemistry 04/2006; 139(3):583-90. · 2.37 Impact Factor
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ABSTRACT: A reversed-phase high performance liquid chromatographic method was developed for the simultaneous quantitative determination of caffeine, dapsone and chlorzoxazone. The operation was carried out on a C18 column (250 mm x 4.6 mm i.d., 5.0 microns) with the mobile phase of acetonitrile-phosphate buffer (including 0.02 mol/L KH2PO4 and 0.02 mol/L (C2H5)3N, pH 6.5) (25:75 in volume ratio). The eluate was detected at 265 nm in 0 min-12 min and at 280 nm in 12 min-25 min. Excellent linearity was observed over the effective concentration ranges in plasma. This method is simple, fast and can be applicable to clinical safe prescription.
Se pu = Chinese journal of chromatography / Zhongguo hua xue hui 12/2002; 20(6):540-2.
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ABSTRACT: Berberine, an isoquinoline alkaloid isolated from several medicinal plants, has been reported to possess anti-bacterial, anti-inflammatory and antitumor properties. Although berberine also inhibits osteoclastogenesis and bone resorption, the molecular machinery for its inhibitory effects remains unknown. This study focused on the suppressive effects of berberine on receptor activator of nuclear factor κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis and survival. Berberine inhibited RANKL-mediated osteoclast formation and survival while having no cytotoxic effects on bone marrow macrophages or osteoblastic cells. Berberine attenuated RANKL-induced activation of NF-κB through inhibiting phosphorylation at the activation loop of IκBα kinase β, phosphorylation and degradation of IκBα, and NF-κB p65 nuclear translocation. RANKL-induced Akt phosphorylation was strongly inhibited by berberine; however, neither monocyte/macrophage-colony stimulating factor (M-CSF)-induced nor insulin-induced Akt activation was inhibited by the drug. Under M-CSF- and RANKL-deprived condition, berberine increased the active form of caspase-3 in osteoclasts. By contrast, berberine did not potentiate the activation of caspase-3 in M-CSF-deprived bone marrow macrophages. These findings indicate that berberine inhibits osteoclast formation and survival through suppression of NF-κB and Akt activation and that both pathways in the osteoclast lineage are highly sensitive to berberine treatment.
European Journal of Pharmacology.
