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Ming Xue - One of the best experts on this subject based on the ideXlab platform.
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development of long circulating Lapachol nanoparticles formation characterization pharmacokinetics distribution and cytotoxicity
RSC Advances, 2020Co-Authors: Qunying Chen, Lu Bai, Yuming Zhao, Xuelin Zhou, Yuanyuan Zheng, Ming XueAbstract:Lapachol is an active compound for the treatment of malignant brain glioma. However, its physicochemical properties limit its clinical application. The purpose of this study is to develop a nano-drug delivery system (LPC-LP) loaded with Lapachol (LPC), which remarkably prolongs the half-life in the body, and increases the brain intake, therefore, achieving a better anticancer effect in the treatment of glioma. In order to optimize the formulation of liposomes, an orthogonal design was adopted with entrapment efficiency (EE) as the index. The characterization of the optimized formulation was evaluated in vitro. To assess the safety profile and effect of LPC-LP, a rapid and sensitive ultra-fast liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method was developed for studying the pharmacokinetics and brain distribution of LPC-LP and LPC. Finally, the cytotoxicity of the two preparations on C6 cells was studied by the MTT assay. The results showed that the average particle size of LPC-LP was 85.92 ± 2.35 nm, the EE of liposomes was 92.52 ± 1.81%, and the charge potential was −40.70 ± 9.20 mV. An in vitro release study showed that the release of Lapachol from LPC-LP was delayed compared to LPC, indicating that LPC-LP was a sustained and controlled release system. The UPLC-MS/MS method was fully validated in both plasma and brain tissue according to the Food and Drug Administration (FDA) recommended guidelines, and successfully used for quantification of Lapachol in vivo. After intravenous administration, LPC-LP prolonged circulation time of Lapachol in the body and increased brain intake. Besides, the MTT results revealed that the IC50 value of LPC-LP on C6 cells significantly decreased, compared with LPC, which further confirmed that LPC-LP enhanced the inhibition of C6 cells and improved the anti-glioma effect. In conclusion, LPC-LP could serve as a promising candidate for the clinical application of Lapachol in the treatment of glioma.
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plasma pharmacokinetics and brain distribution kinetics of Lapachol in rats using lc ms and microdialysis techniques
RSC Advances, 2017Co-Authors: Lu Bai, Ying Han, Binbin Xia, Yuming Zhao, Ming XueAbstract:The objective of this paper was to investigate the plasma pharmacokinetics and brain distribution kinetics of Lapachol in rats. A sensitive and specific high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for quantification of the bioactive naphthoquinone Lapachol in rat plasma and brain dialysates after oral administration. The analytes were determined using the negative electrospray ionization mode in multiple reaction monitoring (MRM). The chromatographic separation was on a ZORBAX SB-C18 column coupled with a C18 guard column using a mobile phase composed of acetonitrile–water containing 0.1% formic acid at a flow rate of 0.5 mL min−1. The methods were sensitive with good linearity and no endogenous material interferences. The inter- and intra-day precision and accuracy of Lapachol in plasma and the brain were lower than 12%. The methods were successfully applied to the quantification and pharmacokinetic study of Lapachol in rats. The results indicated that the disposition profile of Lapachol fitted to first order elimination and the two-compartment open model. Lapachol could pass through the blood brain barrier and went through enterohepatic circulation in rats with extending in vivo exposure time after oral administration. In summary, these findings provide an important pharmacological foundation for developing a novel drug and the clinical use of Lapachol.
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inhibitory effects of Lapachol on rat c6 glioma in vitro and in vivo by targeting dna topoisomerase i and topoisomerase ii
Journal of Experimental & Clinical Cancer Research, 2016Co-Authors: Qunying Chen, Hong Wang, Ru Yuan, Lu Bai, Ming XueAbstract:Lapachol is a natural naphthoquinone compound that possesses extensive biological activities. The aim of this study is to investigate the inhibitory effects of Lapachol on rat C6 glioma both in vitro and in vivo, as well as the potential mechanisms. The antitumor effect of Lapachol was firstly evaluated in the C6 glioma model in Wistar rats. The effects of Lapachol on C6 cell proliferation, apoptosis and DNA damage were detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS)/ phenazinemethosulfate (PMS) assay, hoechst 33358 staining, annexin V-FITC/PI staining, and comet assay. Effects of Lapachol on topoisomerase I (TOP I) and topoisomerase II (TOP II) activities were detected by TOP I and TOP II mediated supercoiled pBR322 DNA relaxation assays and molecular docking. TOP I and TOP II expression levels in C6 cells were also determined. High dose Lapachol showed significant inhibitory effect on the C6 glioma in Wistar rats (P < 0.05). It was showed that Lapachol could inhibit proliferation, induce apoptosis and DNA damage of C6 cells in dose dependent manners. Lapachol could inhibit the activities of both TOP I and II. Lapachol-TOP I showed relatively stronger interaction than that of Lapachol-TOP II in molecular docking study. Also, Lapachol could inhibit TOP II expression levels, but not TOP I expression levels. These results showed that Lapachol could significantly inhibit C6 glioma both in vivo and in vitro, which might be related with inhibiting TOP I and TOP II activities, as well as TOP II expression.
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structural elucidation of the metabolites of Lapachol in rats by liquid chromatography tandem mass spectrometry
Journal of Chromatography B, 2014Co-Authors: Lu Bai, Ying Han, Jinfeng Yao, Ming XueAbstract:Lapachol is a natural naphthoquinone compound derived from Bignoniaceae (Tabebuia sp.) that possesses a range of significant biological activities. Nine phase I and four phase II metabolites of Lapachol in rat bile were firstly elucidated and identified using a sensitive LC-ESI-MS(n) method. The molecular structures of the metabolites have been presented on the basis of the characteristics of their precursor and product ions, as well as their fragmentation mechanisms and chromatographic retention times. The results indicated that the phase I metabolites were predominantly biotransformed by the hydroxylation, semiquinone hydrogenation at the oxygen position or a side chain rearrangement. The phase II metabolites were identified as the glucuronidated conjugates which showed a characteristic neutral loss of 176Da. Based on the results of this research, we have proposed the metabolic pathways for Lapachol in rats. This work has provided novel information for the in vivo Lapachol metabolism which could be used to develop a novel drug candidate, as well as a better understanding of the safety and efficacy of the drug.
Norberto Peporine Lopes - One of the best experts on this subject based on the ideXlab platform.
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understanding the fragmentation mechanisms of methoxy mesyl and tosyl Lapachol derivatives by computational chemistry and mass spectrometry analysis
International Journal of Mass Spectrometry, 2017Co-Authors: Ricardo Vessecchi, Flavio Da Silva Emery, Leticia Da Silva Borges, Norberto Peporine LopesAbstract:Abstract Quinone derivatives are promising anticancer, antimalarial, and antileishmanial drug candidates. Lapachol is the main natural quinonoid compound studied to date. The synthesis of Lapachol (2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone) derivatives can help characterization of these compounds in biological matrixes or extracts, particularly by electrospray ionization tandem mass spectrometry (ESI–MS/MS). The synthesized 2-methoxy-, 2-tosyl- and 2-mesyl- derivatives were protonated and fragmented by collisional-induced dissociation (CID); their fragmentation mechanisms were proposed based on CID results and DFT calculations. Quantum Theory of Atoms-in-Molecules, QTAIM, was performed and the bond weakening/reinforcement from bond critical point analysis of electronic densities was used to suggest the fragmentation pathways. Results herein were compared to data previously reported for Lapachol (2-hydroxy-1,4-naphthoquinone). The tosyl derivative underwent an interesting fragmentation mechanism, which was comparable to the mechanism undergone by protonated Lapachol. Therefore, identifying these compounds by the product-ions produced during ESI–MS/MS spectrometry is feasible.
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gas phase reactivity of 2 hydroxy 1 4 naphthoquinones a computational and mass spectrometry study of Lapachol congeners
Journal of Mass Spectrometry, 2012Co-Authors: Ricardo Vessecchi, Flavio Da Silva Emery, Sergio E Galembeck, Norberto Peporine LopesAbstract:In order to understand the influence of alkyl side chains on the gas-phase reactivity of 1,4-naphthoquinone derivatives, some 2-hydroxy-1,4-naphthoquinone derivatives have been prepared and studied by electrospray ionization tandem mass spectrometry in combination with computational quantum chemistry calculations. Protonation and deprotonation sites were suggested on the basis of gas-phase basicity, proton affinity, gas-phase acidity (ΔGacid), atomic charges and frontier orbital analyses. The nature of the intramolecular interaction as well as of the hydrogen bond in the systems was investigated by the atoms-in-molecules theory and the natural bond orbital analysis. The results were compared with data published for Lapachol (2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone). For the protonated molecules, water elimination was verified to occur at lower proportion when compared with side chain elimination, as evidenced in earlier studies on Lapachol. The side chain at position C(3) was found to play important roles in the fragmentation mechanisms of these compounds. Copyright © 2012 John Wiley & Sons, Ltd.
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biomimetic in vitro oxidation of Lapachol a model to predict and analyse the in vivo phase i metabolism of bioactive compounds
European Journal of Medicinal Chemistry, 2012Co-Authors: Michael Niehues, Flavio Da Silva Emery, V P Barros, Marcelo Diasbaruffi, Marilda Das Dores Assis, Norberto Peporine LopesAbstract:Abstract The bioactive naphtoquinone Lapachol was studied in vitro by a biomimetic model with Jacobsen catalyst (manganese(III) salen) and iodosylbenzene as oxidizing agent. Eleven oxidation derivatives were thus identified and two competitive oxidation pathways postulated. Similar to Mn(III) porphyrins, Jacobsen catalyst mainly induced the formation of para -naphtoquinone derivatives of Lapachol, but also of two ortho -derivatives. The oxidation products were used to develop a GC–MS (SIM mode) method for the identification of potential phase I metabolites in vivo . Plasma analysis of Wistar rats orally administered with Lapachol revealed two metabolites, α -lapachone and dehydro-α-lapachone. Hence, the biomimetic model with a manganese salen complex has evidenced its use as a valuable tool to predict and elucidate the in vivo phase I metabolism of Lapachol and possibly also of other bioactive natural compounds.
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fragmentation studies and electrospray ionization mass spectrometry of Lapachol protonated deprotonated and cationized species
Rapid Communications in Mass Spectrometry, 2010Co-Authors: Flavio Da Silva Emery, Ricardo Vessecchi, Sergio E Galembeck, Norberto Peporine LopesAbstract:Electrospray ionization mass spectrometric analysis of Lapachol (2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone) was accomplished in order to elucidate the gas-phase dissociation reactions of this important biologically active natural product. The occurrence of protonated and cationized species in the positive mode and of deprotonated species in the negative mode was explored by means of collision-induced dissociation (CID) experiments. For the protonated molecule, the H2O and C4H8 losses occur by two competitive channels. For the deprotonated molecule, the even-electron rule is not conserved, and the radicalar species are eliminated by formation of distonic anions. The fragmentation mechanism for each ion was suggested on the basis of computational thermochemistry. Atomic charges, relative energies, and frontier orbitals were employed aiming at a better understanding of the gas-phase reactivity of Lapachol. Potential energy surfaces for fragmentation reactions were obtained by the B3LYP/6-31+G(d,p) model. Copyright © 2010 John Wiley & Sons, Ltd.
Marilia O F Goulart - One of the best experts on this subject based on the ideXlab platform.
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antileishmanial activity of Lapachol analogues
Memorias Do Instituto Oswaldo Cruz, 2004Co-Authors: Nadja M F Lima, Antonio Euzebio Goulart Santana, C S Correia, Leonor L Leon, Gerzia M C Machado, Madeira Mde F, Marilia O F GoulartAbstract:The antileishmanial activity of Lapachol, isoLapachol, and dihydroLapachol, along with soluble derivatives (potassium salt) and acetate was obtained. All the compounds were assayed against metacyclic promastigotes of two different species of Leishmania associated to tegumentar leishmaniasis: L. amazonensis and L. braziliensis. All compounds presented significant activity, being isoLapachol acetate the most active against promastigotes, with IC50/24h = 1.6 ± 0.0 µg/ml and 3.4 ± 0.5 µg/ml for, respectively, L. amazonensis and L. braziliensis. This compound was also assayed in vivo against L. amazonensis and showed to be active. Its toxicity in vitro was also established, and at concentration similar to the IC50, no toxicity was evidenced. In all experiments, pentamidine isethionate was used as a reference drug. The present results reinforce the potential use of substituted hydroxyquinones and derivatives as promising antileishmanial drugs and suggest a continuing study within this class of compounds.
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antimalarial activity of phenazines from Lapachol β lapachone and its derivatives against plasmodium falciparum in vitro and plasmodium berghei in vivo
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Valter Ferreira De Andradeneto, Maria Do Carmo F R Pinto, Marilia O F Goulart, Jorge F Da Silva Filho, Matuzalem J Da Silva, Antonio V Pinto, Mariano G Zalis, Luzia H Carvalho, Antoniana U KrettliAbstract:The antimalarial activity of benzo[a]phenazines synthesized from 1,2-naphthoquinone, Lapachol, beta-lapachone and several derivatives have been tested against Plasmodium falciparum in vitro using isolates of parasites with various susceptibilities to chloroquine and/or mefloquine. Parasite growth in the presence of the test drugs was measured by incorporation of [(3)H]-hipoxanthine in comparison to controls with no drugs, always testing in parallel chloroquine, a standard antimalarial. Among seven benzophenazines tested, four had significant in vitro activities; important, the parasites resistant to chloroquine were more susceptible to the active phenazines in vitro. The doses of phenazines causing 50% inhibition of parasite growth varied from 1.67 to 9.44 microM. The two most active ones were also tested in vivo against Plasmodium berghei in mice, in parallel with Lapachol and beta-lapachone. The 3-sulfonic acid-beta-lapachone-derived phenazine was the most active causing up to 98% inhibition of parasitaemia in long term treatment (7 doses) subcutaneously, whereas the phenazine from 3-bromo-beta-lapachone was inactive. Thus, these simple phenazines, containing polar (-Br,-I) and ionizable (-SO(3)H, -OH) groups, easily synthesized from cheap, natural or synthetic precursors (Lapachol and beta-lapachone), at rather low cost, provide prototypes for development of new antimalarials aiming the chloroquine resistant parasites.
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electrochemical study of oxygen interaction with Lapachol and its radical anions
Bioelectrochemistry, 2003Co-Authors: Marilia O F Goulart, Piotr Falkowski, Tadeusz Ossowski, Adam LiwoAbstract:Abstract Cyclovoltammetric studies were performed with Lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone], in the absence and presence of oxygen, which aimed to investigate possible oxygen interaction with Lapachol and its radical anion. The obtained results clearly indicate the consumption of the semiquinone anion-radicals by oxygen in an EC type reaction, generating the deprotonated form of Lapachol and HOO · . The observed generation of reactive oxygen species (ROS) after electron transfer can be related to the mechanism of biological action of Lapachol.
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toxicity of Lapachol and isoLapachol and their potassium salts against biomphalaria glabrata schistosoma mansoni cercariae artemia salina and tilapia nilotica
Acta Tropica, 2002Co-Authors: Nadja M F Lima, Marilia O F Goulart, Aldenir Feitosa Dos Santos, Zenaldo Porfirio, Antonio Euzebio Goulart SantanaAbstract:The toxicity of soluble derivatives (potassium salt) of Lapachol and isoLapachol in different stages of the life cycle of Schistosoma mansoni is evaluated. The potassium salts of isoLapachol and Lapachol showed significant molluscicidal activity against the adult snail (LC90<7 ppm) and snail egg masses (LC90<3 ppm). Cercaricidal assays revealed strong activities for both compounds. Lethality assays against brine shrimp eggs (Artemia salina Leach) indicated very high toxicity for the potassium salt of isoLapachol (LC90=1.54 ppm), differently from the potassium salt of Lapachol that can be considered non toxic (LC90=176.3 ppm). The same tendency is observed with piscicidal activity, for which the isoLapachol salt has showed higher toxicity. The obtained selectivity ratios concerning LC50 and LC90 for Lapachol, in relation to Tilapia nilotica lethality assay are 2.33 and 1.26, respectively. Despite the piscicidal toxicity, the use of the salt of Lapachol can be recommended for field tests in Schistosomiasis, with caution.
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molluscicidal and trypanocidal activities of Lapachol derivatives
Planta Medica, 2001Co-Authors: Aldenir Feitosa Dos Santos, Marilia O F Goulart, Patricia A L Ferraz, Fabiane C De Abreu, Egler Chiari, Antonio Euzebio Goulart SantanaAbstract:The activity of the potassium salt of Lapachol against the snail Biomphalaria glabrata and its egg masses was tested. The obtained IC50 values (2.70 ppm and 1.43 ppm, respectively) are indicative of a strong activity. Lapachol derivatives were also assayed against infective trypomastigote blood forms of T. cruzi and the triacetoxy derivative of reduced Lapachol showed relevant trypanocidal activity, killing 95.7% of the parasites at the concentration of 42 microg/mL.
Antonio Euzebio Goulart Santana - One of the best experts on this subject based on the ideXlab platform.
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antileishmanial activity of Lapachol analogues
Memorias Do Instituto Oswaldo Cruz, 2004Co-Authors: Nadja M F Lima, Antonio Euzebio Goulart Santana, C S Correia, Leonor L Leon, Gerzia M C Machado, Madeira Mde F, Marilia O F GoulartAbstract:The antileishmanial activity of Lapachol, isoLapachol, and dihydroLapachol, along with soluble derivatives (potassium salt) and acetate was obtained. All the compounds were assayed against metacyclic promastigotes of two different species of Leishmania associated to tegumentar leishmaniasis: L. amazonensis and L. braziliensis. All compounds presented significant activity, being isoLapachol acetate the most active against promastigotes, with IC50/24h = 1.6 ± 0.0 µg/ml and 3.4 ± 0.5 µg/ml for, respectively, L. amazonensis and L. braziliensis. This compound was also assayed in vivo against L. amazonensis and showed to be active. Its toxicity in vitro was also established, and at concentration similar to the IC50, no toxicity was evidenced. In all experiments, pentamidine isethionate was used as a reference drug. The present results reinforce the potential use of substituted hydroxyquinones and derivatives as promising antileishmanial drugs and suggest a continuing study within this class of compounds.
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toxicity of Lapachol and isoLapachol and their potassium salts against biomphalaria glabrata schistosoma mansoni cercariae artemia salina and tilapia nilotica
Acta Tropica, 2002Co-Authors: Nadja M F Lima, Marilia O F Goulart, Aldenir Feitosa Dos Santos, Zenaldo Porfirio, Antonio Euzebio Goulart SantanaAbstract:The toxicity of soluble derivatives (potassium salt) of Lapachol and isoLapachol in different stages of the life cycle of Schistosoma mansoni is evaluated. The potassium salts of isoLapachol and Lapachol showed significant molluscicidal activity against the adult snail (LC90<7 ppm) and snail egg masses (LC90<3 ppm). Cercaricidal assays revealed strong activities for both compounds. Lethality assays against brine shrimp eggs (Artemia salina Leach) indicated very high toxicity for the potassium salt of isoLapachol (LC90=1.54 ppm), differently from the potassium salt of Lapachol that can be considered non toxic (LC90=176.3 ppm). The same tendency is observed with piscicidal activity, for which the isoLapachol salt has showed higher toxicity. The obtained selectivity ratios concerning LC50 and LC90 for Lapachol, in relation to Tilapia nilotica lethality assay are 2.33 and 1.26, respectively. Despite the piscicidal toxicity, the use of the salt of Lapachol can be recommended for field tests in Schistosomiasis, with caution.
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molluscicidal and trypanocidal activities of Lapachol derivatives
Planta Medica, 2001Co-Authors: Aldenir Feitosa Dos Santos, Marilia O F Goulart, Patricia A L Ferraz, Fabiane C De Abreu, Egler Chiari, Antonio Euzebio Goulart SantanaAbstract:The activity of the potassium salt of Lapachol against the snail Biomphalaria glabrata and its egg masses was tested. The obtained IC50 values (2.70 ppm and 1.43 ppm, respectively) are indicative of a strong activity. Lapachol derivatives were also assayed against infective trypomastigote blood forms of T. cruzi and the triacetoxy derivative of reduced Lapachol showed relevant trypanocidal activity, killing 95.7% of the parasites at the concentration of 42 microg/mL.
Lu Bai - One of the best experts on this subject based on the ideXlab platform.
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development of long circulating Lapachol nanoparticles formation characterization pharmacokinetics distribution and cytotoxicity
RSC Advances, 2020Co-Authors: Qunying Chen, Lu Bai, Yuming Zhao, Xuelin Zhou, Yuanyuan Zheng, Ming XueAbstract:Lapachol is an active compound for the treatment of malignant brain glioma. However, its physicochemical properties limit its clinical application. The purpose of this study is to develop a nano-drug delivery system (LPC-LP) loaded with Lapachol (LPC), which remarkably prolongs the half-life in the body, and increases the brain intake, therefore, achieving a better anticancer effect in the treatment of glioma. In order to optimize the formulation of liposomes, an orthogonal design was adopted with entrapment efficiency (EE) as the index. The characterization of the optimized formulation was evaluated in vitro. To assess the safety profile and effect of LPC-LP, a rapid and sensitive ultra-fast liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method was developed for studying the pharmacokinetics and brain distribution of LPC-LP and LPC. Finally, the cytotoxicity of the two preparations on C6 cells was studied by the MTT assay. The results showed that the average particle size of LPC-LP was 85.92 ± 2.35 nm, the EE of liposomes was 92.52 ± 1.81%, and the charge potential was −40.70 ± 9.20 mV. An in vitro release study showed that the release of Lapachol from LPC-LP was delayed compared to LPC, indicating that LPC-LP was a sustained and controlled release system. The UPLC-MS/MS method was fully validated in both plasma and brain tissue according to the Food and Drug Administration (FDA) recommended guidelines, and successfully used for quantification of Lapachol in vivo. After intravenous administration, LPC-LP prolonged circulation time of Lapachol in the body and increased brain intake. Besides, the MTT results revealed that the IC50 value of LPC-LP on C6 cells significantly decreased, compared with LPC, which further confirmed that LPC-LP enhanced the inhibition of C6 cells and improved the anti-glioma effect. In conclusion, LPC-LP could serve as a promising candidate for the clinical application of Lapachol in the treatment of glioma.
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plasma pharmacokinetics and brain distribution kinetics of Lapachol in rats using lc ms and microdialysis techniques
RSC Advances, 2017Co-Authors: Lu Bai, Ying Han, Binbin Xia, Yuming Zhao, Ming XueAbstract:The objective of this paper was to investigate the plasma pharmacokinetics and brain distribution kinetics of Lapachol in rats. A sensitive and specific high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for quantification of the bioactive naphthoquinone Lapachol in rat plasma and brain dialysates after oral administration. The analytes were determined using the negative electrospray ionization mode in multiple reaction monitoring (MRM). The chromatographic separation was on a ZORBAX SB-C18 column coupled with a C18 guard column using a mobile phase composed of acetonitrile–water containing 0.1% formic acid at a flow rate of 0.5 mL min−1. The methods were sensitive with good linearity and no endogenous material interferences. The inter- and intra-day precision and accuracy of Lapachol in plasma and the brain were lower than 12%. The methods were successfully applied to the quantification and pharmacokinetic study of Lapachol in rats. The results indicated that the disposition profile of Lapachol fitted to first order elimination and the two-compartment open model. Lapachol could pass through the blood brain barrier and went through enterohepatic circulation in rats with extending in vivo exposure time after oral administration. In summary, these findings provide an important pharmacological foundation for developing a novel drug and the clinical use of Lapachol.
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inhibitory effects of Lapachol on rat c6 glioma in vitro and in vivo by targeting dna topoisomerase i and topoisomerase ii
Journal of Experimental & Clinical Cancer Research, 2016Co-Authors: Qunying Chen, Hong Wang, Ru Yuan, Lu Bai, Ming XueAbstract:Lapachol is a natural naphthoquinone compound that possesses extensive biological activities. The aim of this study is to investigate the inhibitory effects of Lapachol on rat C6 glioma both in vitro and in vivo, as well as the potential mechanisms. The antitumor effect of Lapachol was firstly evaluated in the C6 glioma model in Wistar rats. The effects of Lapachol on C6 cell proliferation, apoptosis and DNA damage were detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS)/ phenazinemethosulfate (PMS) assay, hoechst 33358 staining, annexin V-FITC/PI staining, and comet assay. Effects of Lapachol on topoisomerase I (TOP I) and topoisomerase II (TOP II) activities were detected by TOP I and TOP II mediated supercoiled pBR322 DNA relaxation assays and molecular docking. TOP I and TOP II expression levels in C6 cells were also determined. High dose Lapachol showed significant inhibitory effect on the C6 glioma in Wistar rats (P < 0.05). It was showed that Lapachol could inhibit proliferation, induce apoptosis and DNA damage of C6 cells in dose dependent manners. Lapachol could inhibit the activities of both TOP I and II. Lapachol-TOP I showed relatively stronger interaction than that of Lapachol-TOP II in molecular docking study. Also, Lapachol could inhibit TOP II expression levels, but not TOP I expression levels. These results showed that Lapachol could significantly inhibit C6 glioma both in vivo and in vitro, which might be related with inhibiting TOP I and TOP II activities, as well as TOP II expression.
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structural elucidation of the metabolites of Lapachol in rats by liquid chromatography tandem mass spectrometry
Journal of Chromatography B, 2014Co-Authors: Lu Bai, Ying Han, Jinfeng Yao, Ming XueAbstract:Lapachol is a natural naphthoquinone compound derived from Bignoniaceae (Tabebuia sp.) that possesses a range of significant biological activities. Nine phase I and four phase II metabolites of Lapachol in rat bile were firstly elucidated and identified using a sensitive LC-ESI-MS(n) method. The molecular structures of the metabolites have been presented on the basis of the characteristics of their precursor and product ions, as well as their fragmentation mechanisms and chromatographic retention times. The results indicated that the phase I metabolites were predominantly biotransformed by the hydroxylation, semiquinone hydrogenation at the oxygen position or a side chain rearrangement. The phase II metabolites were identified as the glucuronidated conjugates which showed a characteristic neutral loss of 176Da. Based on the results of this research, we have proposed the metabolic pathways for Lapachol in rats. This work has provided novel information for the in vivo Lapachol metabolism which could be used to develop a novel drug candidate, as well as a better understanding of the safety and efficacy of the drug.
