I'd like to look at a related question: why don't we inhibit all the metabolisers of levodopa?

I'm posting in this thread, rather than start a new one, because a lot of the background information is contained in previous posts to this thread. In particular (in Post 11) the following table showing 5 metabolism routes for levodopa, not just the normal two: DCC, COMT)

DDC, 70%, Dopamine
COMT, 10%, 3-O-Methyldopa
TAT, ?, 3,4-Dihydroxphenylpyruvic acid
Tyrosinase, ?, Dopa quinone
PST, ?, Conjugation products

At first sight, inhibiting metabolisers which are responsible for a small part of the metabolism seems likely to have only a small impact. But, depending on where you are starting from, this reasoning is incorrect. Suppose that you have two metabolisers A and B responsible for 80% and 10% of metabolism respectively. Then introducing B after A reduces the rate of metabolism from where we are now by half. For instance, going from L/C to L/C/E has this impact [1]:

"Compared with conventional levodopa, the pharmacokinetic profile of levodopa with dual enzyme inhibition [L/C/E, Stalevo] is markedly improved, increasing the half-life of levodopa by up to 85% and the bioavailability of the drug by 35% in plasma".

Given this, from where we are now, inhibiting the other levodopa metabilisers, is likely to have a big effect.

Why is this important? Not to save on the size of the dose. But, to extend the half-life, thus cutting down the variability of plasma levels, which are thought to contribute to dyskinesia.

[1] "Optimizing levodopa therapy for Parkinson’s disease with levodopa/carbidopa/entacapone: implications from a clinical and patient perspective"
D. Brooks
Neuropsychiatric Disease and Treatment, 2008
Optimizing levodopa therapy for Parkinson’s disease with levodopa/carbidopa/entacapone: implications from a clinical and patient perspective

John