Pharmacokinetics and brain distribution studies of 6-hydroxykynurenic acid and its structural modified compounds

2021 ◽  
Author(s):  
Zhuowei Shen ◽  
Haihong Hu ◽  
Jie Pan ◽  
Mingcheng Xu ◽  
Fengting Ou ◽  
...  
Keyword(s):  
Oral Administration ◽  
Brain Homogenate ◽  
Ultra Performance Liquid Chromatography ◽  
Rat Plasma ◽  
Isopropyl Ester ◽  
Brain Distribution ◽  
Apparent Permeability ◽  
Apparent Permeability Coefficient ◽  
Distribution Studies ◽  
The Brain

Abstract Objectives 6-Hydroxykynurenic acid (6-HKA) is an organic acid component in extracts of Ginkgo biloba leaves and acts as a major contributor to neurorestorative effects, while its oral bioavailability was low. Therefore, using prodrug method to improve the bioavailability and brain content of 6-HKA is significant. Methods Three structural modified compounds of 6-HKA were synthesized, and ultra performance liquid chromatography-tandem mass spectrometry methods for quantification of these structural modified compounds in rat plasma and rat brain homogenate were established and comprehensively validated. The methods were effectively applied to investigate the effects of structural modification on apparent permeability coefficients in cells, the pharmacokinetics and the brain distribution in rats. Key findings The results illustrated that esterification can greatly improve the apparent permeability coefficient and bioavailability of 6-HKA. Comparing with direct oral administration of 6-HKA, the bioavailability of isopropyl ester was greatly improved (from 3.96 ± 1.45% to 41.8 ± 15.3%), and the contents of 6-HKA in rat brains (49.7 ± 9.2 ng/g brain) were significantly higher after oral administration. Conclusions The bioavailability and the brain content of 6-HKA can be improved by the prodrug method. Among three structural modified compounds, isopropyl-esterified 6-HKA was the most promising treatment.

scholarly journals Simultaneous Quantification of Brigatinib and Brigatinib-Analog in Rat Plasma and Brain Homogenate by LC-MS/MS: Application to Comparative Pharmacokinetic and Brain Distribution Studies

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Bo Li ◽  
Min Lu ◽  
Lei Jin ◽  
Maoen Zheng ◽  
Peilu Sun ◽  
...  
Keyword(s):  
High Performance ◽  
Brain Homogenate ◽  
Gradient Elution ◽  
Rat Plasma ◽  
Brain Distribution ◽  
Single Oral Administration ◽  
Mass Spectrometric Detector ◽  
Distribution Studies ◽  
Lower Limits

Brigatinib and brigatinib-analog are potent and selective ALK inhibitors with the similar structure. A simple and sensitive high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of brigatinib and brigatinib-analog in rat plasma and brain homogenate was developed and validated. Chromatographic separation was carried out on an ODS column with acetonitrile and 0.1% formic acid in water as the mobile phase with gradient elution at a flow rate of 0.5 mL/min. Detections were performed using a TSQ Quantum Ultra mass spectrometric detector with electrospray ionization (ESI) interface, which was operated in the positive ion mode. A simple protein precipitation preparation process was used. The lower limits of quantification (LLOQs) were 1.0 ng/mL and 0.5 ng/mL for analytes in rat plasma and brain homogenate, respectively. The intrabatch and interbatch precision and accuracy of brigatinib and brigatinib-analog were well within the acceptable limits of variation. The simple and sensitive LC-MS/MS method was successfully applied to the pharmacokinetic and brain distribution studies following a single oral administration of brigatinib and brigatinib-analog to rats. The above studies would lay a good foundation for the further applications of brigatinib and brigatinib-analog.

Simultaneous Determination of Imatinib and N-Desmethyl Imatinib in Rat Plasma and Tissues Using LC-MS/MS

2019 ◽  
Vol 15 (2) ◽  
pp. 121-129
Author(s):  
Zhi Rao ◽  
Bo-xia Li ◽  
Yong-Wen Jin ◽  
Wen-Kou ◽  
Yan-rong Ma ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Oral Administration ◽  
Parent Drug ◽  
Gradient Elution ◽  
Biological Tissues ◽  
Rat Plasma ◽  
Running Water ◽  
Liver And Kidney ◽  
The Brain

Background: Imatinib (IM) is a chemotherapy medication metabolized by CYP3A4 to Ndesmethyl imatinib (NDI), which shows similar pharmacologic activity to the parent drug. Although methods for determination of IM and/or NDI have been developed extensively, only few observations have been addressed to simultaneously determine IM and NDI in biological tissues such as liver, kidney, heart, brain and bone marrow. Methods: A validated LC-MS/MS method was developed for the quantitative determination of imatinib (IM) and N-desmethyl imatinib (NDI) from rat plasma, bone marrow, brain, heart, liver and kidney. The plasma samples were prepared by protein precipitation, and then the separation of the analytes was achieved using an Agilent Zorbax Eclipse Plus C18 column (4.6 × 100 mm, 3.5 µm) with gradient elution running water (A) and methanol (B). Mass spectrometric detection was achieved by a triplequadrupole mass spectrometer equipped with an electrospray source interface in positive ionization mode. Results: This method was used to investigate the pharmacokinetics and the tissue distributions in rats following oral administration of 25 mg/kg of IM. The pharmacokinetic profiles suggested that IM and NDI are disappeared faster in rats than human, and the tissue distribution results showed that IM and NDI had good tissue penetration and distribution, except for the brain. This is the first report about the large penetrations of IM and NDI in rat bone marrow. Conclusion: The method demonstrated good sensitivity, accuracy, precision and recovery in assays of IM and NDI in rats. The described assay was successfully applied for the evaluation of pharmacokinetics and distribution in the brain, heart, liver, kidney and bone marrow of IM and NDI after a single oral administration of IM to rats.

scholarly journals Pharmacokinetics of 10-Hydroxy Mesaconitine in Rat Plasma by Ultra-Performance Liquid Chromatography-Tandem Quadrupole Mass Spectrometry

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Jinzhao Yang ◽  
Guowu Zeng ◽  
Jianshe Ma ◽  
Xianqin Wang ◽  
Quan Zhou
Keyword(s):  
Oral Administration ◽  
Matrix Effects ◽  
Ultra Performance Liquid Chromatography ◽  
Rat Plasma ◽  
Quadrupole Mass ◽  
Standard Curve ◽  
The Matrix ◽  
Intravenous And Oral Administration ◽  
T Values ◽  
Tandem Quadrupole

Mesaconitine is the predominant active ingredient in Aconitum carmichaelii Debx. The compound 10-hydroxy mesaconitine is one known metabolite of mesaconitine and is toxic. In order to better understand its pharmacokinetics, UPLC-MS/MS was used in this paper to measure the concentration of 10-hydroxy mesaconitine in the plasma of rats after oral (5 mg/kg) and intravenous (0.1 mg/kg) administration of 10-hydroxy mesaconitine. The concentrations of 10-hydroxy mesaconitine in rat plasma measured in the standard curve covered the range of 0.3–60 ng/mL. The intraday and interday precisions of the samples of 10-hydroxy mesaconitine in rat plasma were lower than 15%. In addition, the accuracies ranged between 96.0% and 109.3%, the matrix effects ranged between 88.9% and 98.1%, and the recoveries were all higher than 79.1%. The AUC(0 − t) values were 23.6 ± 5.9 and 207.6 ± 72.9 ng/mL·h for intravenous and oral administration, respectively, and the bioavailability of 10-hydroxy mesaconitine was 17.6%. Lastly, t1/2 was 1.3 ± 0.6 h and 3.1 ± 0.4 h for intravenous and oral administration, respectively.

scholarly journals Profiling and Pharmacokinetic Studies of Alkaloids in Rats After Oral Administration of Zanthoxylum nitidum Decoction by UPLC-Q-TOF-MS/MS and HPLC-MS/MS

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 585 ◽  
Author(s):  
Aihua Huang ◽  
Yuguang Chi ◽  
Jiawei Liu ◽  
Mincun Wang ◽  
Jialiang Qin ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Oral Administration ◽  
High Performance ◽  
Ultra Performance Liquid Chromatography ◽  
Rat Plasma ◽  
Pharmacokinetic Studies ◽  
Flight Mass Spectrometry ◽  
Zanthoxylum Nitidum

Zanthoxylum nitidum (Roxb.) DC (Rutaceae), called as “liangmianzhen” in China, is well known for its anti-inflammation and analgesic effect. Alkaloids are its main active constituents. However, little has been known about the absorption of main alkaloids in vivo. In this study, an ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry was employed for identification of absorbed alkaloids in rats after oral administration of Z. nitidum decoction. By analyzing the fragmentation patterns, a total of nineteen alkaloids were exactly or tentatively identified in rat plasma after treatment, of which magnoflorine, α-allocryptopine, and skimmianine are dominant. Moreover, a high performance liquid chromatography coupled mass spectrometry method was developed for simultaneous quantification of magnoflorine, α-allocryptopine, and skimmianine, and successfully applied to pharmacokinetic study in rats after oral administration of Z. nitidum decoction. The research would contribute to comprehensive understanding of the material basis and function mechanism of Z. nitidum decoction.

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