In vitro hepatic biotransformation of moclobemide (Ro 11-1163) in man and rat.

1. Moclobemide, an inhibitor of monoamine oxidase, shows mixed MAO A/B inhibition in rat, but pure MAO A inhibition in man. This is attributed to a primary amine metabolite which inhibits MAO B in vitro, but which is not detected in human plasma in vivo. A secondary amine metabolite, also present in rat but not human plasma, inhibitors MAO B in vivo but not in vitro. 2. We have studied the biotransformation of moclobemide in vitro, to investigate whether hepatocytes and hepatic subcellular fractions can reproduce the in vivo interspecies differences. 3. Moclobemide was more extensively metabolized by rat liver preparations, compared with man. For example, of an initial 100 nmol, 78 and 25 nmol were metabolized within 24 h by rat and human hepatocytes in primary culture, respectively. 4. Substantial amounts of secondary amine (12.5 nmol) were found with the rat preparation, compared with low amounts (1.5 nmol) from human hepatocytes. Similarly, for the primary amine, 1.5 nmol were formed by the rat hepatocytes compared with trace amount in the human preparations. 5. Identities of the two amines were confirmed by h.p.l.c. cochromatography and negative CI GC-MS. 6. In conclusion, all the in vitro models, but particularly hepatocytes, reflected the metabolism of moclobemide in vivo. Consequently, liver preparations can be used prospectively to screen the selectivity of related development compounds.