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

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 IC 50 (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 –CH 2 and –CO 2 , the loss of –CH 2 O, ester bond hydrolysis, the loss of –O and –CO 2 , isomerization, methylation, sulfate conjugation, the loss of –CH 2 O and –O and glycine conjugation, glycine conjugation, the loss of two –O groups and alanine conjugation, the loss of –CH 2 O and –O and glucose conjugation, glucuronidation, glucose conjugation, etc., in vivo. Finally, MDHB has a low probability of cytochrome P450-based DDIs.