On the reversibility of reversible MAO inhibitors

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Abstract
The aim of this study was to assess a) the validity of an ex vivo approach for the estimation of the in vivo MAO A inhibitory properties of the new short-acting MAO A inhibitors, amiflamine, brofaremine, cimoxatone and moclobemide, by studying the effect of dilution of brain and liver homogenates from pretreated rats on the degree of enzyme inhibition; b) the displaceability of the inhibitors from the enzyme by substrate in brain and liver homogenates from pretreated rats; c) idem, in the in vivo situation in the brain, by increasing the availability of the substrate by releasing it from its endogenous stores by tetrabenazine. The following results were obtained: The ex vivo approach was found to be valid for moclobemide in brain and liver and for cimoxatone in brain tissue; a slight underestimation of the MAO A inhibitory effect of the latter in the liver is likely. Definite underestimation occurred with amiflamine in both tissues. Kinetic investigations using homogenates from pretreated rats showed amiflamine to be a competitive inhibitor; cimoxatone was competitive in the liver but showed a more complex pattern in the brain. Moclobemide was noncompetitive in both tissues, as has been shown previously for brofaremine. Moclobemide prevented the deamination of dopamine and serotonin released from their striatal stores by tetrabenazine nearly as efficiently as clorgyline at an otherwise equieffective dose; cimoxatone was somewhat less effective relative to the reference compound, as was brofaremine, which was however given at a more effective dose. Amiflamine was much less effective than clorgyline at protecting dopamine, but equieffective with respect to serotonin. These differences might be of clinical relevance, since the ease with which the inhibitors can be displaced by an increased concentration of an endogenous substrate might effect both therapeutic efficacy and probability of unwanted effects.