Originally Posted by johnt

See the diagram below:

Attachment 9833

A simple model using the pharmacokinetic properties of levodopa suggests that when the drug is at its highest concentration, about a hour after being taken orally, plasma levels are approximately 4 times higher than is immediately required.

The model makes many simplifications. Notably it does not capture that levodopa's pharmacokinetic parameters will vary from time to time and from person to person. Nevertheless, the model does seem to reasonably reflect my experience of using levodopa, and the model does seem to show some interesting features of levodopa therapy.

When taken orally a dose of levodopa (taken with carbidopa) progresses through the stomach into the upper intestines where it is gradually absorbed. Peak plasma levels are typically found about 60 minutes (TMAX) after the drug is taken. Thereafter, plasma levels halve about every 90 minutes (THALF).

In broad strokes, the pharmacodynamic effect of this on us is that immediately after taking a dose there is no benefit from the levodopa. Then, after about 15 - 60 minutes the drug kicks in, often quite suddenly, and we go from "off" to "on". It is as though there is a threshold that needs to be crossed to get any benefit. After this we can expect about three to four hours of "on" time before, again often quite suddenly, we go "off".

For a person who has no significant endogenous production and storage of dopamine, a major part of the movement process is being controlled by the exogenous levodopa. Therefore, the only way to stay "on" is to keep plasma levels above the threshold level. To do this, one dose must be responsible for 3 to 4 hours of "on" time. The only way that this can be done using standard delivery mechanisms is to overshoot the threshold. Taking us just to the threshold gives us only an instant of "on" time as the concentration immediately begins to drop. Taking us to twice the threshold gives us: half the time to maximum dose (about 30 minutes) plus one half-life of duration (about 90 minutes) for a total of 120 minutes of "on" time. Taking us to four times gives us three quarters of the time to maximum concentration (about 45 minutes) plus two half-lives of duration (about 3 hours), for a total of about 225 minutes of "on" time.

For someone still producing and storing dopamine the overshoot will be reduced.

What are the effects of having such high levels of levodopa, which fluctuate through the course of each dose? Why is the norm not to take more frequent, but smaller doses?

John