Simultaneous quantitation of 3-n-butylphthalide (NBP) and its four major metabolites in human plasma by LC–MS/MS using deuterated internal standards

Diao, Xingxing; Ma, Zhiyu; Wang, Haidong; Zhong, Dafang; Zhang, Yifan; Jin, Jing; Fan, Yaxin; Chen, Xiaoyan

doi:10.1016/j.jpba.2013.01.033

Cited by 46 publications

(28 citation statements)

References 23 publications

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“…It is recommended to use a stable isotope-labeled analog as internal standard for quantitative LC–MS/MS analysis [11] and [12]. The best peak response was attained with acetonitrile and water with 0.1% FA as opposed to 0% and 0.2% FA.…”

Section: Resultsmentioning

confidence: 99%

Simultaneous determination and validation of oncrasin-266 and its metabolites by HPLC–MS/MS: Application to a pharmacokinetic study

White

et al. 2016

Journal of Chromatography B

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Oncrasins are a class of RNA polymerase II inhibitors. Oncrasin-72 is an indole-3 carbinol analog that has shown to inhibit growth and induce the cell death of various human cancer cell lines. Oncrasin-266, a prodrug of oncrasin-72, has been shown to have improved pharmacokinetic properties and safety than Oncrasin-72. With respect to the potential therapeutic advantages of this class of compounds, there is a need for further preclinical assessment for future clinical trials. The development of and validation of an analytical method is essential for the quantification of oncrasins in biological fluids for pharmacokinetic studies. This study focuses on the LC-MS/MS method development and validation of oncrasin-266, oncrasin-72 and its aldehyde metabolite in rat plasma. Blank rat plasma, coupled with 1-(3-chlorobenzyl)-1H-indole, as internal standard, was used for generating standard curves ranging from 1–250 ng/mL for oncrasin-266 and oncrasin-72; and 0.5–125 ng/mL for the aldehyde metabolite. The chromatographic separation was achieved by a Zorbax 300SB-C18 HPLC column at 50°C with a flow rate of 1.1 mL/min under gradient elution. Mass detection was performed under positive ionization electrospray. Intra- and inter-day accuracy and precision of the assay were less than 10%. We report a simple, specific and reproducible LC-MS/MS method for the quantification of oncrasins in rat plasma. This study was successfully used for the quantification of oncrasins in rat plasma for pharmacokinetic studies in three dose groups of 10, 25, and 50 mg/kg via intravenous administration.

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Section: Resultsmentioning

confidence: 99%

Simultaneous determination and validation of oncrasin-266 and its metabolites by HPLC–MS/MS: Application to a pharmacokinetic study

White

et al. 2016

Journal of Chromatography B

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“…To improve the chromatographic stability of the analytes, 10 mM ammonium formate was added to the mobile phase. [16] The peak tailing and wide peak shape was observed when the chromatography was in the isocratic elution.…”

Section: Optimization Of Mass Spectrometric and Chromatographic Condimentioning

confidence: 99%

Development and validation of a UPLC–MS/MS method for quantitation of droxidopa in human plasma: Application to a pharmacokinetic study

Wang

Yang

Zhou

et al. 2016

Journal of Chromatography B

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“…We previously reported that NBP undergoes extensive metabolism in humans after a single dose of 200 mg NBP in soft capsules [8] . The major circulating metabolites found were 3-hydroxy-NBP (3-OH-NBP), 10-hydroxy-NBP (10-OH-NBP), 10-keto-NBP (10-CO-NBP), and NBP-11-oic acid [8,9] . The areas under the concentration-time curves (AUC) for 3-OH-NBP and 10-OH-NBP were 2.9 and 10.3 times greater, respectively, than that of NBP [9] .…”

Section: -N-butylphthalide (Nbp (±)-3-butyl-1(3h)-isobenzofuranone)mentioning

confidence: 99%

“…The major circulating metabolites found were 3-hydroxy-NBP (3-OH-NBP), 10-hydroxy-NBP (10-OH-NBP), 10-keto-NBP (10-CO-NBP), and NBP-11-oic acid [8,9] . The areas under the concentration-time curves (AUC) for 3-OH-NBP and 10-OH-NBP were 2.9 and 10.3 times greater, respectively, than that of NBP [9] . Because NBP is used to treat cerebral diseases, we also attempted to study the metabolite profile of NBP in rat brain.…”

Section: -N-butylphthalide (Nbp (±)-3-butyl-1(3h)-isobenzofuranone)mentioning

confidence: 99%

“…The concentrations of 3-OH-NBP and 10-OH-NBP were determined using a Shimadzu LC-20AD HPLC system (Kyoto, Japan) coupled to an API4000 triple quadrupole MS (Sciex, Ontario, Canada) that was equipped with a TurboIonSpray ion source. Chromatographic separation was achieved on a Zorbax XDB- Acta Pharmacologica Sinica npg C 18 column (50×4.6 mm, id, 1.8 µm; Agilent, Santa Clara, CA, USA) under gradient elution as previously described [9] . The MS was operated in the negative-positive switch mode: 0-3.5 min, (−)ESI for 3-OH-NBP and (+)ESI for 10-OH-NBP from 3.5-8.0 min.…”

Section: Animalsmentioning

confidence: 99%

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Isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP and 10-hydroxy-NBP, across the rat blood-brain barrier

Diao

Zhong

et al. 2015

Acta Pharmacol Sin

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Aim: To investigate the mechanisms underlying the isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP (3-OH-NBP) and 10-hydroxy-NBP (10-OH-NBP), across the blood brain barrier (BBB). Methods: After oral administration of NBP (20 mg/kg) to rats, the pharmacokinetics of two major hydroxylated metabolites, 3-OH-NBP and 10-OH-NBP, in plasma and brains were investigated. Plasma and brain protein binding of 3-OH-NBP and 10-OH-NBP was also assessed. To evaluate the influences of major efflux transporters, rats were pretreated with the P-gp inhibitor tariquidar (10 mg/kg, iv) and BCRP inhibitor pantoprazole (40 mg/kg, iv), then received 3-OH-NBP (12 mg/kg, iv) or 10-OH-NBP (3 mg/kg, iv). The metabolic profile of NBP was investigated in rat brain homogenate. Results: After NBP administration, the plasma exposure of 3-OH-NBP was 4.64 times that of 10-OH-NBP, whereas the brain exposure of 3-OH-NBP was only 11.8% of 10-OH-NBP. In the rat plasma, 60%±5.2% of 10-OH-NBP was unbound to proteins versus only 22%±2.3% of 3-OH-NBP being unbound, whereas in the rat brain, free fractions of 3-OH-NBP and 10-OH-NBP were 100%±9.7% and 49.9%±14.1%, respectively. In the rats pretreated with tariquidar and pantoprazole, the unbound partition coefficient K p,uu of 3-OH-NBP was significantly increased, while that of 10-OH-NBP showed a slight but not statistically significant increase. Incubation of rat brain homogenate with NBP yielded 3-OH-NBP but not 10-OH-NBP. Conclusion: The isomer-selective distribution of 10-OH-NBP and 3-OH-NBP across the BBB of rats is mainly attributed to the differences in plasma and brain protein binding and the efflux transport of 3-OH-NBP. The abundant 10-OH-NBP is not generated in rat brains.

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Simultaneous quantitation of 3-n-butylphthalide (NBP) and its four major metabolites in human plasma by LC–MS/MS using deuterated internal standards

Cited by 46 publications

References 23 publications

Simultaneous determination and validation of oncrasin-266 and its metabolites by HPLC–MS/MS: Application to a pharmacokinetic study

Simultaneous determination and validation of oncrasin-266 and its metabolites by HPLC–MS/MS: Application to a pharmacokinetic study

Development and validation of a UPLC–MS/MS method for quantitation of droxidopa in human plasma: Application to a pharmacokinetic study

Isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP and 10-hydroxy-NBP, across the rat blood-brain barrier

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