deprenyl MAOB 50% enzyme inactivation and other questions/some waffle.

[selegimuppet]

Hello,

Hope I've posted this in the right section.

I initially tried a simplistic approach to try and work this out: a person has a certain amount of MAOB doing its thing in the brain and it is cycled slowly enough that it can be approximated as not being in an equilibrium with regeneration/inactivation over a short time scale. Basically there are just a certain number of protein molecules there.

5mg of deprenyl (mol wt: 187.3 g/mol) is 0.005/187.281 = 0.0000267 moles, Avogadros number: 6.02214?1023 mol−1 x 0.0000267 = 1.6 x 1019 molecules. That's a shitload, I can't imagine that many large proteins so much deprenyl must be bound up, metabolised, unavailable and this will be variable between individuals.

Well I'm none the wiser after that so I'll just ask outright! Does anyone know vaguely, the dose required to fully saturate MAOB (and no more), and a dose that will only HALF saturate MAOB?

Are there noticable possitive effects at partial blockade?

Surely it is safer to maintain some of this pathway operating?

Does the body compensate for Deprenyl binding by synthesising increasing amounts of MAOB? A tolerance effect.

All the best!

 

[Weltmeister]

MAO exists in all human tissues, except redblood cells. MAO protects the intestines and liver against the effects of exogenous biogenic amines,whereas in other tissues, such as the brain, it breaksdown mediator substances and thus control their concentrations. Two subtypes of MAO, A and B, have been recognised. In humans, most tissues contain both MAO-A and MAO-B. The placenta contains predominantly MAO-A, while platelets and lymphocytes contain only MAO-BP7l How-ever, the brain possesses both forms P6l MAO-B contributes about 80% of the total MAO activity in the human brain and is responsible for the metabolism of dopamine in the human brain. The substrates for MAO-A include serotonin,adrenaline and noradrenaline, whereas the substrates for MAO-B include benzylamine, phenylethylamine and kynuramine. Tyramine, tryptamineand 3-methoxy-tyramine are substrates for both enzymes. However, the substrate specificity is not absolute and in a number of cases exceptions were found. Inhibition of MAO-B can also be demonstrated by the increase of the excretion of phenylethylamine in the urine. Selegiline therapy increases the excretion of phenylethylamine in urine and this can be used as an alternative method for the evaluation of MAO-B inhibition following selegiline administration.There are a variety of compounds which can inhibit monoamine oxidases. Inhibition of MAO leads to an increase of aromatic amines in the brain and other organs of the body. MAO inhibitors can interact with enzyme reversibly or irreversibly. A reversible inhibitor of MAO forms a complex with the enzyme which can be reversed by procedures that reduce the concentration of free inhibitors. The reversible inhibitors can be removed from the system by dialysis or by simple dilution to restore full enzymatic activity. The duration of the effect of a reversible MAO inhibitor in vivo will depend upon how rapidly the inhibitor is removed from the body by metabolism or another biochemical process. An irreversible inhibitor binds to the active site of the enzyme by an irreversible process and cannot be subsequently dissociated from it. A covalent bond is generally formed between the inhibitor and the enzyme. Irreversible inhibitors cannot be removed by dialysis and the degree of inhibition by an irreversible inhibitor increases over time. Selegiline is an irreversible inhibitor of MAOB. Selegiline binds covalently to the flavin part[flavin adenin dinucleotide (FAD)] of MAO.After this irreversible binding is formed MAO cannot be activated by dialysis or gel filtration.The human platelet possesses mitochondrial MAO-B, similar to the major form of MAO-Bfound in human brain. MAO-B is selectively inhibitedby selegiline and thus human platelets can beused as a peripheral model to indirectly assess thedegree and duration of MAO-B inhibition occurringin the CNS. In a study conducted by Lee et al MAO-B activity in the platelets of 79 patients with Parkinson's disease was evaluated before and during selegiline therapy. Within 2 to 4 hours after the first oral dose of selegiline 5mg,86% inhibition of MAO-B activity was noted,whereas after 24 hours the inhibition was 98%. An oral dose of selegiline 10mg given once a day produced similar effects as observed with an oraldose of selegiline 5mg given twice a day. Inhibition of platelet activity remained at over 90%for 5 days, returning to baseline levels within 14days. The recovery of MAO-B activity following inhibition by selegiline is dose, organ and species dependent. Considering that following a single oral dose of selegiline 10mg, the MAO-B activity in platelets returns to normal in 2 weeks, it appears that besides inhibition of MAO-B activity, other factors may contribute to the clinical efficacy of selegiline. Though selegiline is selective for MAO-B, this selectivity can be lost at high therapeutic dosages(more than 20mg) in humans. In the post mortem brain of 7 expatients who had received selegiline 10mg/day for a mean of 6 days before death,the brain MAO-A activity was inhibited between 38 to 86%.

https://link.springer.com/article/10.2165/00003088-199733020-00002