In vitro and in vivo pharmacokinetic and pharmacodynamic study of MBRI-001, a deuterium-substituted plinabulin derivative as a potent anti-cancer agent

Ma, Mingxu; Zhao, Jianchun; Cheng, Hejuan; Ding, Zhongpeng; Hou, Yingwei; Li, Feng; Dou, Guifang; Li, Wenbao

doi:10.1016/j.bmc.2018.08.009

Cited by 8 publications

(4 citation statements)

References 23 publications

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“…MBRI-001 showed better efficacy against cancer growth with lower toxicity in mice than docetaxel. 35 , 36 The combination of MBRI-001 with gefitinib showed a significant antitumor effect than monotherapy. 35 The combination of MBRI-001 and sorafenib showed a better antitumor activity that may provide a new approach for treating HCC in the future.…”

Section: Mbri-001: a Deuterated Plinabulinmentioning

confidence: 99%

“… 35 , 36 The combination of MBRI-001 with gefitinib showed a significant antitumor effect than monotherapy. 35 The combination of MBRI-001 and sorafenib showed a better antitumor activity that may provide a new approach for treating HCC in the future. 36 Therefore, MBRI-001 could be the most promising anti-cancer agent in the future.…”

Section: Mbri-001: a Deuterated Plinabulinmentioning

confidence: 99%

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Recent Updates on the Development of Deuterium-Containing Drugs for the Treatment of Cancer

Belete¹

2022

DDDT

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Cancer is one of the deadliest diseases in the world. In 2020, 19.3 million cancer cases and 10 million deaths were reported in the world. It is supposed that the prevalence of cancer cases will rise to 28.4 million by 2040. Chemotherapy-based regimens have a narrow therapeutic index, severe adverse drug reactions, and lack metabolic stability. Besides, the metabolism of anticancer produces several non-active and toxic metabolites that reduce exposure of the target site to the parent drug. Therefore, developing better-tolerated and effective new anticancer drugs and modification of the existing anticancer drugs to minimize toxicity and increase efficacy has become a very urgent need. Deuterium incorporation reduces the metabolism of certain drugs that are breakdown by pathways involving hydrogen-carbon bond scission. For example, CYP450 mediated oxidative metabolism of drugs that involves the breakdown of a hydrogen-carbon bond affected by deuteration. Deuterium incorporation into the drug increases the half-life and reduces the dose, which provides better safety and efficacy. Deutetrabenazine is the first deuterated form of tetrabenazine approved to treat chorea associated with Huntington’s disease and tardive dyskinesia. The study revealed that Deutetrabenazine has fewer neuropsychiatric side effects with favorable safety than tetrabenazine. The current review highlights the deuterium kinetic isotope effect on drug metabolism, deuterated compound pharmacokinetic property, and safety profile. Besides, this review explains the deuterated anticancer drug development update status.

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Section: Mbri-001: a Deuterated Plinabulinmentioning

confidence: 99%

Section: Mbri-001: a Deuterated Plinabulinmentioning

confidence: 99%

Recent Updates on the Development of Deuterium-Containing Drugs for the Treatment of Cancer

Belete¹

2022

DDDT

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“…Although plinabulin is in phase III clinical trials, few references and preclinical data in vivo have been published [ 9 ]. Until now, only a preclinical study of MBRI-001, a deuterium-substituted plinabulin derivative, has been published [ 10 ]. MBRI-001 exhibits pharmacokinetic profiles quite different from plinabulin in vitro, and all the data of plinabulin are in vitro results [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…Until now, only a preclinical study of MBRI-001, a deuterium-substituted plinabulin derivative, has been published [ 10 ]. MBRI-001 exhibits pharmacokinetic profiles quite different from plinabulin in vitro, and all the data of plinabulin are in vitro results [ 10 ]. All available reports are about plinabulin combined with other drugs, and all studies are based on health status [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Development and Validation of a Novel UHPLC-MS/MS Method for the Quantification of Plinabulin in Plasma and Its Application in a Pharmacokinetic Study with Leukopenic Rats

Niu

Chen

et al. 2023

Pharmaceuticals

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Plinabulin, a new antitumor drug developed from marine natural products that targets microtubules in cancer cells, is currently being tested in a phase III clinical study. Plinabulin has been clinically proven to be effective on leukopenia. However, to our knowledge, there are no reports investigating the pharmacokinetics of plinabulin in individuals with leukopenia and healthy individuals. In this study, we developed a rapid and sensitive UHPLC-MS/MS method for the detection of plinabulin for the first time. Using a novel cyclophosphamide-induced leukopenia model, we investigated the differences in the pharmacokinetic characteristics of plinabulin between rats with leukopenia and normal rats. Plinabulin and propranolol (IS) peaks were separated by gradient elution for a total run time of 5 min. The methodological validation showed a good accuracy (101.96–109.42%) and precision (RSD ≤ 5.37%) with the lower limit of quantification at 0.5 ng/mL. The recovery of plinabulin was between 91.99% and 109.75% (RSD ≤ 7.92%). The values of the area under the plasma concentration-time curve (AUC0-t) for leukopenia groups and control groups at doses of 0.5 mg/kg, 1 mg/kg, and 3 mg/kg were 148.89 ± 78.74 h·μg/L and 121.75 ± 31.56 h·μg/L; 318.15 ± 40.00 h·μg/L and 272.06 ± 42.85 h·μg/L; and 1432.43 ± 197.47 h·μg/L and 1337.12 ± 193.56 h·μg/L; respectively. The half-lives (t1/2s) of plinabulin were 0.49–0.72 h for leukopenia groups and 0.39–0.70 h for control groups at three doses, and the clearance rates (CLs) of plinabulin were 2.13–3.87 L/h/kg for leukopenia groups and 2.29–4.23 L/h/kg for control groups. Pharmacokinetic results showed that there was no significant pharmacokinetic difference between the normal group and the leukopenia group. Based on the power model, plinabulin exhibits a lack of dose proportionality over the dose range of 0.5–3 mg/kg after intravenous administration. This study provides guidance for the development of plinabulin as a potential candidate for the treatment of chemotherapy-induced leukopenia.

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Involvement of ER stress and reactive oxygen species generation in anti-cancer effect of CKD-516 for lung cancer

Kim

Jegal

et al. 2020

Cancer Chemother Pharmacol

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In vitro and in vivo pharmacokinetic and pharmacodynamic study of MBRI-001, a deuterium-substituted plinabulin derivative as a potent anti-cancer agent

Cited by 8 publications

References 23 publications

Recent Updates on the Development of Deuterium-Containing Drugs for the Treatment of Cancer

Recent Updates on the Development of Deuterium-Containing Drugs for the Treatment of Cancer

Development and Validation of a Novel UHPLC-MS/MS Method for the Quantification of Plinabulin in Plasma and Its Application in a Pharmacokinetic Study with Leukopenic Rats

Involvement of ER stress and reactive oxygen species generation in anti-cancer effect of CKD-516 for lung cancer

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