In vitro enantioselective metabolism of TJ0711 hydrochloride by human liver microsomes using a novel chiral liquid chromatography–tandem mass spectrometry method

Huang, Jiangeng; Hu, Lei; Xu, Li; Sun, Minghui; Fan, Zhaoze; Qiu, Jun; Gao, Li; Si, Luqin

doi:10.1016/j.jchromb.2012.02.018

Cited by 6 publications

(9 citation statements)

References 8 publications

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“…The LLOQ was determined as 0.5 ng/mL, with an ideal signal-to-noise ratio (>20) and acceptable precision and accuracy (Table 1), which was sufficiently sensitive for the quantification and pharmacokinetic analysis of TJ0711 in dog plasma. This method offered significantly higher sensitivity and broader dynamic range (1000-fold) compared with our previous methods (Fan et al, 2010;Huang et al, 2011Huang et al, , 2012Sun et al, 2009).…”

Section: Methods Developmentmentioning

confidence: 78%

Accurate determination of a novel vasodilatory β‐blocker TJ0711 using LC‐MS/MS: Resolution of an isobaric metabolite interference in dog plasma

Zhu

Guan

et al. 2018

Biomedical Chromatography

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A rapid, robust and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for bioanalysis of TJ0711, a novel vasodilatory β-blocker in dog plasma. This assay is able to chromatographically separate TJ0711 from its isobaric metabolite as well as glucuronide conjugates. Chromatographic separation was achieved on a Welch Ultimate-XB C column (2.1 × 100 mm, 3 μm). The analyte and internal standard (propranolol) were extracted from plasma by liquid-liquid extraction using ethyl acetate. The mass spectrometric detection was carried out in positive ion multiple reaction monitoring mode. Good linearity was obtained over the concentration range of 0.5-500 ng/mL (r > 0.99) for TJ0711. Moreover, the method had good accuracy (RE ranging from -2.70 to -0.32%) and precision (RSD < 7.55%). TJ0711 was stable in dog plasma for at least 6 h at ambient temperature, for at least 30 days at -20°C and after three freeze-thaw cycles. This method was successfully applied to a preclinical pharmacokinetic study and the results demonstrated linear pharmacokinetics of TJ0711 over a dose range from 0.03 to 0.3 mg/kg. No significant gender differences were observed in TJ0711 plasma pharmacokinetic parameters.

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Section: Methods Developmentmentioning

confidence: 78%

Accurate determination of a novel vasodilatory β‐blocker TJ0711 using LC‐MS/MS: Resolution of an isobaric metabolite interference in dog plasma

Zhu

Guan

et al. 2018

Biomedical Chromatography

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“…Preferential metabolism of R-TJ0711 was observed in the in vitro metabolism of TJ0711 hydrochloride by human liver microsomes, and both TJ0711 enantiomers were classified as high-extraction-ratio compounds since extraction ratio values of R-TJ0711 (0.81) and S-TJ0711 (0.71) were larger than 0.7. 16 E H value of rac-TJ0711 hydrochloride was middle (0.55, unpublished) in male SD rats. On the other hand, TJ0711 is a drug with high protein binding (>80%) in male SD rats, 14 and the protein binding differences between the two enantiomers are expected, which would contribute to enantioselectivity in the elimination rate.…”

Section: Discussionmentioning

confidence: 90%

“…1). 16 A moderate enantioselectivity of TJ0711 hydrochloride pharmacokinetics has been mentioned in rats, 17 but the effects of dose and route of administration on the enantioselective pharmacokinetic characteristics of TJ0711 hydrochloride have not been investigated. Like many other chiral compounds, the pharmacokinetics of TJ0711 enantiomers in a body may be different.…”

Section: -[4-(2-methoxyethyl)phenoxy]-3-[[2-(2-methoxyphenoxy)ethyl]mentioning

confidence: 99%

“…R-TJ0711 is preferentially metabolized by human liver microsomes compared with S-TJ0711 in vitro. 16 A moderate enantioselectivity of TJ0711 hydrochloride pharmacokinetics has been mentioned in rats, 17 but the effects of dose and route of administration on the enantioselective pharmacokinetic characteristics of TJ0711 hydrochloride have not been investigated. Therefore, in order to clarify the enantioselective behavior of TJ0711 hydrochloride in vivo and further develop the single enantiomer as a new drug candidate to reduce dosage and side effects, it is necessary to study the effects of dose and route of administration on the enantioselective pharmacokinetics of TJ0711 hydrochloride.…”

Section: Introductionmentioning

confidence: 99%

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Influence of Dose and Route of Administration on the Enantioselective Pharmacokinetics of TJ0711 Hydrochloride in Rats

Sun

Fan

et al. 2014

Chirality

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The enantioselective pharmacokinetics of TJ0711 hydrochloride were studied in rats given different doses of rac-TJ0711 hydrochloride via intravenous and oral routes. R- and S-TJ0711 hydrochloride were both rapidly absorbed, and the average AUC0-∞ of R-TJ0711 hydrochloride was greater than that of S-TJ0711 hydrochloride after intragastric administration, with an R/S AUC ratio 1.11 and 1.35 for 30 and 50 mg/kg dose group, respectively. In contrast, the average AUC0-∞ of R-TJ0711 hydrochloride was smaller than that of S-TJ0711 hydrochloride after intravenous injection, with an R/S AUC ratio 0.57 and 0.73 for 10 and 20 mg/kg dose group, respectively. R-TJ0711 hydrochloride plasma half-lives were shorter than those of S-TJ0711 hydrochloride for all groups. AUC0-4h and Cmax between the two enantiomers were significantly different after oral administration of 50 mg/kg dose of the racemate, while no significant differences between the two enantiomers were found for all the pharmacokinetic parameters of the 30 mg/kg dose group. Significant differences between the two enantiomers were detected for nearly all the pharmacokinetic parameters after intravenous administration, except for the VZ of 20 mg/kg dose group. This study suggests that dose and route of administration will influence the enantioselectivity in the pharmacokinetics of TJ0711 hydrochloride in rats.

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“…MRM–information dependent acquisition–enhanced product ion (MRM‐IDA‐EPI) scans were used for the identification of the metabolites, which resulted in the identification of a higher number of metabolites compared with neutral loss (NL), precursor ion (PI), and enhanced mass spectrometry (EMS) scans. The details of our approach in metabolite identification were described previously (Huang et al ., , ; Zheng et al ., ). Briefly, EPI spectra of analytes were collected to identify the three most abundant fragments for each analyte.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics, protein binding and metabolism of a quinoxaline urea analog as an NF‐κB inhibitor in mice and rats by LC‐MS/MS

Gautam

Bathena

Chen

et al. 2013

Biomedical Chromatography

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13–197 is a novel NF-ĸB inhibitor that shows promising in-vitro efficacy data against pancreatic cancer. In this study, we characterized the pharmacokinetics (PK), tissue distribution, protein binding, and metabolism of 13–197 in mice and rats. A valid, sensitive, and selective LC-MS/MS method was developed. This method was validated for the quantification of 13–197, in the range of 0.1–500 ng/ml in mouse plasma, liver, kidney, lung, heart, spleen, brain, urine and feces. 13–197 has low bioavailability of 3 and 16% in mice, and rats respectively. 13–197 has faster absorption in mice with 12-fold shorter Tmax than in rats. Tissue concentrations were 1.3–69.2 folds higher in mice than in rats at 72h after intravenous administration. 13–197 is well distributed to the peripheral tissues and has relatively high tissue: plasma concentration ratios, ranging from 1.8 to 3634, in both mice and rats. 13–197 also demonstrated more than 99% binding to plasma proteins in both mice and rats. Finally, less than 1% of 13–197 is excreted unchanged in urine and feces, and metabolite profiling studies detected more than 20 metabolites in mice and rats plasma, urine, and feces, which indicates 13–197 is extensively metabolized and primarily eliminated by metabolism rather than by excretion.

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In vitro enantioselective metabolism of TJ0711 hydrochloride by human liver microsomes using a novel chiral liquid chromatography–tandem mass spectrometry method

Cited by 6 publications

References 8 publications

Accurate determination of a novel vasodilatory β‐blocker TJ0711 using LC‐MS/MS: Resolution of an isobaric metabolite interference in dog plasma

Accurate determination of a novel vasodilatory β‐blocker TJ0711 using LC‐MS/MS: Resolution of an isobaric metabolite interference in dog plasma

Influence of Dose and Route of Administration on the Enantioselective Pharmacokinetics of TJ0711 Hydrochloride in Rats

Pharmacokinetics, protein binding and metabolism of a quinoxaline urea analog as an NF‐κB inhibitor in mice and rats by LC‐MS/MS

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