My understanding regarding DDC inhibitors is as follows:
- if you don't add a DDC inhibitor (i.e. carbidopa/benserazide), you need to use a much larger dose of levodopa, in order for sufficient levodopa to make it into the brain;
- such large doses of levodopa cause unwanted side effects (e.g. nausea).

My understanding regarding COMT inhibitors is that their main function (in PD treatment) is to (try to) stop COMT from breaking down dopamine in the brain.

Jeffreyn,

Thanks for your prompt reply.

I agree when you write:
"- if you don't add a DDC inhibitor (i.e. carbidopa/benserazide), you need to use a much larger dose of levodopa, in order for sufficient levodopa to make it into the brain;
- such large doses of levodopa cause unwanted side effects (e.g. nausea)."

You write:
"My understanding regarding COMT inhibitors is that their main function (in PD treatment) is to (try to) stop COMT from breaking down dopamine in the brain."

I'm not familiar with this process. However, what you describe is the role played by MAO-B inhibitors (e.g. rasagiline) [1].
"Selective MAOB inhibitors ... preferentially [inhibit] MAOB, which mostly metabolizes DA. If MAOB is inhibited, then more DA is available for proper neuronal function, especially in Parkinson's Disease.

In a recent doctorial thesis [2] I've found a reference to the effect of levodopa plus entacapone without carbidopa:
"That the Cmax and AUC of levodopa in both CSF and blood increased significantly when additional entacapone was given alone and in combination with carbidopa. The increase was more evident when entacapone was combined with carbidopa."

Reference:

[1] Monoamine oxidase B - Wikipedia

[2] "Levodopa pharmacokinetics-from stomach to brain"
Maria Nord,
Dissertation, Linkoping University, 2017
https://liu.diva-portal.org/smash/ge...FULLTEXT01.pdf

John

John, it's not just levodopa that the COMT enzyme acts on, it's all the catecholamines as well.

From Wikipedia (see link):
"Catechol-O-methyltransferase (COMT) is one of several enzymes that degrade catecholamines (such as dopamine, epinephrine, and norepinephrine), catecholestrogens, and various drugs and substances having a catechol structure."

Catechol-O-methyl transferase - Wikipedia

In regards to your main point, if you had a drug which contained just levodopa and entacapone, you wouldn't be able to stop the DDC enzyme from converting a lot of the levodopa into dopamine, before the levodopa made it into the brain. The dopamine produced in this way would be of no benefit to the PwP, since dopamine cannot pass through the blood-brain barrier.

i don't think carbidopa and entacapone pass the BBB. if carbidopa entered the brain very little l-dopa would be converted to dopamine in the brain. this feature made carbidopa so attractive and reduced the l-dopa dosage from over 10grams and impractical to use to treat pd for the masses to what it is today.


entacapone also doesn't cross the BBB which makes it less potent than Tolcapone (tasmar) which i think is no longer used in the U.S. over liver toxicity risks and the need to monitor that.

Medscape: Medscape Access
Entacapone is highly protein bound, approximately 98%, with a limited body distribution.[42,44] It has poor brain penetration and predominately peripheral effects, although it may exhibit central effects if given in high doses.[

ST is correct, entacapone has limited ability to pass the BBB. Tolcapone had significantly better absorption in both the body and brain.

Okay, it seems clear now that my understanding of the role played by COMT inhibitors was faulty.

My new understanding is as follows:
The main purpose of COMT inhibitors (in PD treatment) is to (try to) stop the COMT enzyme from breaking down levodopa (mainly outside of the brain).

Johnt, sorry for derailing your thread with my misunderstanding regarding the role of COMT inhibitors. Soccertese and Tupelo3, thanks for helping to clear up that misunderstanding.

John's initial question still stands: why isn't there a drug which just contains levodopa and entacapone?

As I said earlier, my understanding is as follows:
"If you had a drug which contained just levodopa and entacapone, you wouldn't be able to stop the DDC enzyme from converting a lot of the levodopa into dopamine, before the levodopa made it into the brain." Which means you would need to use a lot more levodopa, which means you would get more severe side effects (e.g. nausea).

Is my understanding correct? Are there any other reasons?