Effect of lamotrigine on the activities of monoamine oxidases A and B in vitro and on monoamine disposition in vivo.
Recent clinical evidence indicates that the broad spectrum anticonvulsant drug lamotrigine is effective against the depressive phase of bipolar illness and the difficult to treat rapid cycling form of the disorder. However, the molecular mechanism underlying this therapeutic action remains uncertain. Given that inhibition of the A-type of monoamine oxidase (MAO) is a proven antidepressant mechanism, we investigated the effects of lamotrigine on MAO activities in vitro and on monoamine disposition in vivo. In vitro, lamotrigine inhibited rat brain MAO activities with Ki values (MAO-A, 15 microM; MAO-B, 18 microM) potentially within the therapeutic range for this drug. The effects of lamotrigine on the MAO-A activities of rat brain and human liver preparations were almost identical suggesting minimal species or tissue variation. In contrast, there was no (MAO-A) or minimal (MAO-B) reduction in brain MAO activities when assayed ex vivo following the administration of lamotrigine to rats. In vivo brain microdialysis failed to detect meaningful alterations in extracellular hippocampal or frontal cortex monoamine concentrations. Furthermore, lamotrigine did not modulate oral tyramine-induced hypertension in rats or 5-hydroxytryptophan-induced head shaking in mice, providing strong evidence that the drug does not perturb monoamine metabolism in vivo. The absence of observable effects of lamotrigine on monoamine disposition in vivo may be explained by the competitive and highly reversible nature of the interaction of lamotrigine with MAO isoforms. Thus, altered monoamine metabolism in vivo is unlikely to account for the antidepressant action of the drug in bipolar depression.
Southam
Eric
E
Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park North, Harlow, Essex, CM19 5AW, UK. eric_2_southam@gsk.com
Pereira
Rui
R
Stratton
Sharon C
SC
Sargent
Rebecca
R
Ford
Alison J
AJ
Butterfield
Lindsay J
LJ
Wheable
Jane D
JD
Beckett
Simon R G
SR
Roe
Clare
C
Marsden
Charles A
CA
Hagan
Russell M
RM
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000077213:Lamotrigine; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D017551:Microdialysis; D008995:Monoamine Oxidase / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology*; D014439:Tyramine / Q000494:pharmacology
D000927:Anticonvulsants; D015306:Biogenic Monoamines; D014227:Triazines; D012701:Serotonin; D006916:5-Hydroxytryptophan; D008995:Monoamine Oxidase; D000077213:Lamotrigine; D004298:Dopamine; D009638:Norepinephrine; D014439:Tyramine