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Toloxatone is a drug that selectively and reversibly inhibits monoamine oxidase A (MAO-A) activity on the outer membranes of neuronal mitochondria. It slows the catabolism of monoamines, such as dopamine, norepinephrine, and serotonin, and potentiates their activity in the synaptic cleft. Imbalances in these monoaminergic systems, as well as a significant increase in MAO-A concentrations and activity, have been heavily implicated in major depressive disorders. This drug acts to restore chemical balance in the brain, and therefore is primarily marketed as an antidepressant. It has also been effective in the treatment of mood disorders, manic-depressive disorder, various depressive states, and psychosis.

History
The first MAO inhibitors to be marketed as antidepressants for humans were both nonselective and irreversible. Though they were moderately successful in combatting depression, adverse side effects included hepatotoxicity, orthostatic hypotension, and tyramine-induced hypertensive crisis (also known as the “cheese effect”). It was determined that many of these side effects were due to interactions with hydrazine moieties, which participated in covalent bonding with the active site of MAO, rendering the interaction irreversible.

In 1985, toloxatone was launched as the first reversible inhibitor of MAO-A (RIMA). Its reversibility significantly lowered the number of aversive side effects. Soon after, pharmaceutical companies employed the “piggy-back” approach to targeted drug design, and small modifications were made to the structure of toloxatone. Other RIMAs, such as pirlindole and moclobemide, soon entered the market with even fewer side effects. With the successful development of serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), both of which have fewer adverse side effects, RIMA development has slowed significantly.

Pharmacodynamics
Toloxatone is a reversible inhibitor of MAO-A (RIMA). By inhibiting MAO-A, monoaminergic neurotransmitters are degraded less quickly and their effects in the synapse are potentiated. The drug's affinity for MAO-A is over 100 times greater than MAO-B, rendering it very selective.

Due to their irreversibility, nonselective MAO inhibitors, tolaxatone’s predecessors, could quickly build up to toxic levels in the human body. MAO inhibitors form a reversible complex with FAD, a MAO cofactor, where they are oxidized. After gaining reactivity via oxidation, the inhibitors covalently bind to the enzyme.

In contrast, MAO-A inhibitors’ mechanism of action is still largely unknown. X-ray diffraction crystallography suggests that it is a planar molecule with pi-pi interactions and significant electron delocalization, both of which contribute to the molecule’s stability. Reversible binding interactions are more likely to occur when a molecule exhibits these properties. Additionally, electronic absorption spectroscopy studies have suggested that toloxatone forms a reversible complex with riboflavin.

Pharmacokinetics
Toloxatone is administered orally via a 200 mg tablet three times a day. It has a high hepatic excretion ratio and plasma concentrations are dramatically reduced during the first pass effect, resulting in low bioavailability (50-62%). 87% and 91% of the dose is completely metabolized 8 and 12 hours after administration, respectively. Eventually, the drug undergoes complete hepatic elimination, and less than 1% is excreted unmetabolized. Many of these metabolites are a glucuronide of toloxatone and 3-(3-carboxyphenyl)-5-hydroxymethyl-2-oxazolidinone. Toloxatone’s half-life is very short at 1-3 hours. Maximum plasma concentrations, approximately 1.5 to 3 mg/L, are reached 30-60 minutes after administration. Toloxatone binds extensively with the carrier protein albumin during plasma circulation. The drug is uncharged, and likely passes the blood-brain barrier through passive diffusion. Studies in mice have suggested that a toxic dose is 1500 mg/kg of body weight. Liver-impaired patients often require a dose adjustment because of the hepatic system’s large role in metabolizing this drug.

Side effects
Many of the reported side effects involve gastrointestinal discomfort, dyspepsia, and constipation. These symptoms may be related to the method of administration, since the drug is introduced into the blood stream through absorption in the intestines. Other side effects include headaches, dizziness, delusions, euphoria, aggression, and generalized anxiety. Unlike many other antidepressants, toloxatone does not interfere with memory or sleep patterns.

Availability
Toloxatone was an original structure and the first RIMA to be proven effective in treating depression in humans. As such, it was quickly modified in an effort to improve pharmacokinetic properties. Though toloxatone is extremely selective for MAO-A, other RIMAs have similar selectivity indices, higher potencies, and higher efficacies. Within ten years of toloxatone's introduction to the market, a slew of similar but novel drugs, including befloxatone, brofaromine, BW 1370U87, and RS 8359, had all been synthesized and shown to be more potent MAO-A inhibitors. Additionally, SSRIs have emerged as a class of antidepressant drugs with greater tolerability in humans and wider clinical applications than MAO-A inhibitors. For these reasons, toloxatone has never been manufactured or distributed outside of France, where it was originally synthesized and remains available today.