pH-dependent spontaneous hydrolysis rather than gut bacterial metabolism reduces levels of the ADHD treatment, Methylphenidate

Methylphenidate is absorbed in the small intestine. The drug is known to have low bioavailability and a high interindividual variability in terms of response to the treatment. Gut microbiota has been shown to reduce the bioavailability of a wide variety of orally administered drugs. Here, we tested the ability of small intestinal bacteria to metabolize methylphenidate. In silico analysis identified several small intestinal bacteria to harbor homologues of the human carboxylesterase 1 enzyme responsible for the hydrolysis of methylphenidate in the liver. Despite our initial results hinting towards possible bacterial hydrolysis of the drug, up to 60% of methylphenidate was spontaneously hydrolyzed in the absence of bacteria and this hydrolysis was pH-dependent. Overall, the study shows that pH-dependent spontaneous hydrolysis rather than gut bacterial metabolism reduces levels of methylphenidate and suggest a role of the luminal pH in the bioavailability of the drug.