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Excretion, Metabolism and Cytochrome P450 Inhibition of Methyl 3,4-Dihydroxybenzoate (MDHB): A Potential Candidate to Treat Neurodegenerative Diseases

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Methyl 3,4-dihydroxybenzoate (MDHB) has the potential to prevent neurodegenerative diseases (NDDs). The present work investigated its excretion, metabolism, and cytochrome P450-based drug–drug interactions (DDIs).

Methods

After intragastric administration of MDHB, the parent drug was assayed in the urine and faeces of mice. Metabolites of MDHB in the urine, faeces, brain, plasma and liver were detected by liquid chromatography–hybrid quadrupole time-of-flight mass spectrometry (LC–QTOF/MS). A cocktail approach was used to evaluate the inhibition of cytochrome P450 isoforms by MDHB.

Results

The cumulative excretion permille of MDHB in the urine and faeces were found to be 0.67 ± 0.31 and 0.49 ± 0.44‰, respectively. A total of 96 metabolites of MDHB were identified, and all IC50 (half-maximal inhibitory concentration) values of MDHB towards cytochrome P450 isoforms were > 100 μM.

Conclusions

The results suggest that MDHB has a low parent drug cumulative excretion percentage and that MDHB has multiple metabolites and is mainly metabolized through the loss of –CH2 and –CO2, the loss of –CH2O, ester bond hydrolysis, the loss of –O and –CO2, isomerization, methylation, sulfate conjugation, the loss of –CH2O and –O and glycine conjugation, glycine conjugation, the loss of two –O groups and alanine conjugation, the loss of –CH2O and –O and glucose conjugation, glucuronidation, glucose conjugation, etc., in vivo. Finally, MDHB has a low probability of cytochrome P450-based DDIs.

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Author notes

  1. Jia Hui Wang, Ke Qi Chen and Jun Xing Jiang contributed equally to this study.

Authors and Affiliations

  1. Department of Pharmacology, College of Basic Medicine, Jinan University, Guangzhou, China

    Jia Hui Wang, Ke Qi Chen, Jun Xing Jiang, Jun Ping Pan, Yang Hu, Xiang Nan Mi, Yi Rong Xin, Qin Gao, Fei Xiao & Huan Min Luo

  2. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

    Jia Hui Wang

  3. Analytical and Testing Center, Jinan University, Guangzhou, China

    Huan Yong Li & Lin Wang

  4. State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangzhou, China

    Ji Yan Su

  5. SCIEX (China) Co., Ltd., Guangzhou, China

    Xiang Long Zhao

  6. Institute of Brain Sciences, Jinan University, Guangzhou, China

    Fei Xiao & Huan Min Luo

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  1. Jia Hui Wang
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Corresponding authors

Correspondence to Fei Xiao or Huan Min Luo.

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Ethical approval

The animal experiments adhered to the Jinan University Medical College Animal Use Ordinance and were approved by the Ethics Committee of the Medical School of Jinan University.

Funding

This work was supported by the National Natural Science Foundation of China (grant no. 81473296) and China’s 111 Project (no. B14036).

Conflict of interest

None of the authors have conflicts of interest to declare.

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Wang, J.H., Chen, K.Q., Jiang, J.X. et al. Excretion, Metabolism and Cytochrome P450 Inhibition of Methyl 3,4-Dihydroxybenzoate (MDHB): A Potential Candidate to Treat Neurodegenerative Diseases. Eur J Drug Metab Pharmacokinet 45, 51–69 (2020). https://doi.org/10.1007/s13318-019-00576-6

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