The anticonvulsant FCE 26743 is a selective and short-acting MAO-B inhibitor devoid of inducing properties towards cytochrome P450-dependent testosterone hydroxylation in mice and rats.
The effects of the potent anticonvulsant FCE 26743 ((S)-2-(4-3-fluorobenzyloxy)benzylamino)propionamide) on monoamine oxidase (MAO) activity were measured in-vitro and ex-vivo using rat tissue homogenates. In-vitro, FCE 26743 showed potent and selective inhibitory properties towards liver MAO-B, with IC50 values about 10(-7) M for MAO-B and higher than 10(-5) M for MAO-A. When determined ex-vivo in brain, the ED50 value for the inhibition of MAO-B was 1.1 mg kg-1 (p.o.) 1 h post-dosing, whereas MAO-A remained virtually unaffected after administration of 60 mg kg-1. Similar effects were seen in liver. Following oral administration of 5 mg kg-1 FCE 26743 to rats, brain MAO-B inhibition was 79% after 1 h and 13% after 24 h, indicating that FCE 26743 behaves as a short-acting MAO-B inhibitor. The ability of FCE 26743 to act as a MAO substrate was assessed in mice by measuring the urinary excretion of alaninamide, a potential metabolite of FCE 26743 which would result from the action of MAO. No alaninamide was detectable in the 0-8 h urines after administration of a 119 mg kg-1 dose, suggesting that FCE 26743 is not, or only to a small degree, a substrate of MAO. The effects of FCE 26743 on cytochrome P450 enzymes involved in testosterone hydroxylation were determined in rats after repeated administration. No induction of the cytochrome P450 system was noted.
Strolin Benedetti
M S
MS
Pharmacia-Farmitalia Carlo Erba, Research and Development, Milan, Italy.
Marrari
P
P
Colombo
M
M
Castelli
M G
MG
Arand
M
M
Oesch
F
F
Dostert
P
P
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006900:Hydroxylation; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism*
D000927:Anticonvulsants; D001596:Benzylamines; D008996:Monoamine Oxidase Inhibitors; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; C092797:safinamide; D000409:Alanine