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.