for small molecules that aims to penetrate BBB. how long of a half life is appropriate? Is there a too long or too short half life? how long is too long or too short?
It really depends on the type of molecule and effect that it needs to achieve.
Most molecules that are optimized for BBB penetration suffer greatly from short
T half life values due to extensive metabolism in the liver, CNS, and plasma.
Heroin, as Dr Pardridge mentioned, overcomes the challenge posed by its short half life by quick BBB penetration. Though this property is rare.
In order to overcome short half life values many strategies have been employed.
E.G.:
1) Prodrugs were used as a strategy in molecules like newer amphetamines.
2) Enzyme inhibitors like in carbidopa, COMT and MAO inhibitors.
3) newer strategies like P-GP inhibition and experimental intra-nasal administration.
The case with CNS active drugs is not simply related to their half life values, but more to their duration of action. This is perhaps a better measure than half life. Usually, active metabolites extend the duration of action of a drug which has a short half life.
If we were to take into consideration the half life of the parent molecule collectively with its metabolites. I'd say a short duration of action would be anything under 4 hours, an acceptable duration of action would be up to 24 perhaps even 48 hours, while a long duration of action can reach 100 hours.
How long is appropriate? depends on the indication, patient's adherence, and many other factors. It would be unwise to judge a CNS active drug solely by its half life.
Heroin is an excellent example when compared to morphine. Heroin enter brain at a better rate than morphine as it is acetylated And has a high bbb permeability surface area product. The bbb permeability surface area product is critical.