Simultaneous determination of curcumin diethyl disuccinate and its active metabolite curcumin in rat plasma by LC–MS/MS: Application of esterase inhibitors in the stabilization of an ester-containing prodrug

Bhuket, Pahweenvaj Ratnatilaka Na; Niwattisaiwong, Nuansri; Limpikirati, Patanachai; Khemawoot, Phisit; Towiwat, Pasarapa; Ongpipattanakul, Boonsri; Rojsitthisak, Pornchai

doi:10.1016/j.jchromb.2016.08.039

Cited by 29 publications

(22 citation statements)

References 40 publications

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“…The retention times of CDD and DMC internal standards were 9.8. and 5.7 min, respectively. The peak with a retention time of 9.5 min ( Figure 3) represented a tautomer of CDD, as it exhibited the same mass-to-charge ratio as CDD (m/z 625.2279, mass error 0.1 ppm), which was inferred from studies by Kawano et al (2013), Ratnatilaka Na Bhuket et al (2016, Jia et al (2017), andRatnatilaka Na Bhuket et al (2019). Two metabolites with retention times of 2.5 and 6.3 min were formed and referred to as M1 and M2, respectively.…”

Section: In Vitro Metabolism Profiling Of Curcumin Diethyl Disuccinatementioning

confidence: 86%

In Vitro Hepatic Metabolism of Curcumin Diethyl Disuccinate by Liver S9 from Different Animal Species

et al. 2020

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Liver S9 (LS9) is a nearly complete collection of all hepatic drug-metabolizing enzymes. It is a low-cost model for predicting drug metabolic activity. This study aimed to identify the suitability of using LS9 of different animal sources in drug metabolism profiling with respect to the possible translation of the in vitro outcomes to clinical studies. The in vitro hepatic metabolism of curcumin diethyl disuccinate (CDD) in LS9 of rats, dogs, monkeys, and humans was evaluated. The identity of CDD metabolites and the metabolism kinetic parameters, including degradation rate constant, in vitro / in vivo intrinsic clearance, and half-life, were determined. CDD was rapidly metabolized into monoethylsuccinyl curcumin and curcumin in LS9 of all tested species mainly by carboxylesterases (CESs), including CES1 and CES2, and butyrylcholinesterase. The in vitro intrinsic clearance of CDD was in the order of human > dog > monkey > rat, whereas that of monoethylsuccinyl curcumin in the order of dog > monkey > human > rat; this parameter was not correlated with their respective in vivo clearance, which followed the order of dog > monkey > rat > human. Therefore, in vitro drug metabolism data inferred from LS9 of nonhuman origin, especially from monkeys and dogs, cannot be used as preclinical data for human trials, as humans have a smaller liver-to-body weight ratio than monkeys, dogs, and rats. The in vivo drug metabolism is dictated by the anatomical factors of the test subject.

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Section: In Vitro Metabolism Profiling Of Curcumin Diethyl Disuccinatementioning

confidence: 86%

In Vitro Hepatic Metabolism of Curcumin Diethyl Disuccinate by Liver S9 from Different Animal Species

et al. 2020

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“…1B) is one of our Cur ester prodrugs with improved chemical stability in phosphate buffer pH 7.4 and increased anti-proliferative activity against colon and breast cancer cell lines 25,26 . Pharmacokinetic studies of CurDD showed that CurDD had superior tissue distribution in comparison with Cur and improved an area under the plasma concentration versus time curve of Cur after oral and intravenous administration 27,28 . It also possesses a promising analgesic activity in the peripheral and central anti-nociceptive models in mice 29 .…”

Section: Introductionmentioning

confidence: 99%

Curcumin diethyl disuccinate, a prodrug of curcumin, enhances anti-proliferative effect of curcumin against HepG2 cells via apoptosis induction

Muangnoi

Bhuket

Jithavech

et al. 2019

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Curcumin (Cur) has been reported to have anti-hepatocellular carcinoma activity but its poor oral bioavailability limits its further development as a chemotherapeutic agent. We synthesized previously a succinate ester prodrug of Cur, curcumin diethyl disuccinate (CurDD) with better chemical stability in a buffer solution pH 7.4. Here, we further investigated and compared the cellular transport and anti-proliferative activity against HepG2 cells of CurDD and Cur. Transport of CurDD across the Caco-2 monolayers provided a significantly higher amount of the bioavailable fraction (BF) of Cur with better cytotoxicity against HepG2 cells compared to that of Cur ( p < 0.05). Flow cytometric analysis showed that the BF of CurDD shifted the cell fate to early and late apoptosis to a higher extent than that of Cur. The Western blot analysis revealed that CurDD increased Bax protein expression, downregulated Bcl-2 protein, activated caspase-3 and -9 and increased LC3-II protein level in HepG2 cells. Flow cytometric and immunoblotting results suggest that CurDD can induce HepG2 cell death via an apoptotic pathway. We suggest that CurDD can overcome the limitations of Cur in terms of cellular transport with a potential for further extensive in vitro and in vivo studies of anti-hepatocellular carcinoma effects.

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“…The techniques used for sample analysis are primarily dependent on the instrument availability and the research objective of the study. Table 3 [33,38,39,40,41,42,43,44,45,46,47,48,49,134,135] and Table 4 [14,25,26,27,28,29,30,31,35,36,37,93,96,133,136,137,138,139,140,141,142,143,144,145] summarize the various instrumentation and methods used to study and quantify curcumin in different matrices.…”

Section: Methods For Qualitative and Quantitative Analysismentioning

confidence: 99%

Curcumin: Biological, Pharmaceutical, Nutraceutical, and Analytical Aspects

2019

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Turmeric is a curry spice that originated from India, which has attracted great interest in recent decades because it contains bioactive curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin). Curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-hepta-1,6-diene-3,5-dione), a lipophilic polyphenol may work as an anticancer, antibiotic, anti-inflammatory, and anti-aging agent as suggested by several in vitro, in vivo studies and clinical trials. However, poor aqueous solubility, bioavailability, and pharmacokinetic profiles limit curcumin’s therapeutic usage. To address these issues, several curcumin formulations have been developed. However, suboptimal sample preparation and analysis methodologies often hamper the accurate evaluation of bioactivities and their clinical efficacy. This review summarizes recent research on biological, pharmaceutical, and analytical aspects of the curcumin. Various formulation techniques and corresponding clinical trials and in vivo outcomes are discussed. A detailed comparison of different sample preparation (ultrasonic, pressurized liquid extraction, microwave, reflux) and analytical (FT-IR, FT-NIR, FT-Raman, UV, NMR, HPTLC, HPLC, and LC-MS/MS) methodologies used for the extraction and quantification of curcuminoids in different matrices, is presented. Application of optimal sample preparation, chromatographic separation, and detection methodologies will significantly improve the assessment of different formulations and biological activities of curcuminoids.

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Simultaneous determination of curcumin diethyl disuccinate and its active metabolite curcumin in rat plasma by LC–MS/MS: Application of esterase inhibitors in the stabilization of an ester-containing prodrug

Cited by 29 publications

References 40 publications

In Vitro Hepatic Metabolism of Curcumin Diethyl Disuccinate by Liver S9 from Different Animal Species

In Vitro Hepatic Metabolism of Curcumin Diethyl Disuccinate by Liver S9 from Different Animal Species

Curcumin diethyl disuccinate, a prodrug of curcumin, enhances anti-proliferative effect of curcumin against HepG2 cells via apoptosis induction

Curcumin: Biological, Pharmaceutical, Nutraceutical, and Analytical Aspects

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