Dutasteride And Finasteride, And Their Structures

[BaldingHelpMe]

They are both 5AR competitive inhibitors, and part of their structures look identical. But why is Finasteride has a half-life of only 8 hours and has a flat response curve; while Dutasteride has a half-life of 5 weeks, and it's said to be dose-dependent?

Anyone has a background in chemistry and bioscience wanna explain these two structures, what makes them different? Part of dutasteride's structure contains the entire structure of finasteride, so it looks like dutasteride is "finasteride plus something extra".

Dutasteride:
https://en.wikipedia.org/wiki/Dutasteride#/media/File:Dutasteride.svg
https://pubchem.ncbi.nlm.nih.gov/compound/finasteride#section=Top


Finasteride
https://en.wikipedia.org/wiki/Finasteride#/media/File:Finasteride.svg
https://pubchem.ncbi.nlm.nih.gov/compound/Dutasteride#section=Top

 

[violetfluff]

I'm not qualified to say but I would guess it has to do with inhibition of hydrolysis of the amide linkage due to to steric hindrance.
The tert-butyl group, in the case of finasteride, may be less effective than the p-di(trifluoromethyl)benzene group at blocking the breakage of the amide bond.
Steric hindrance is essentially blocking a chemical reaction by physically blocking at a reaction site due to bulkiness of the group nearby.

Or maybe the difference is the fact that in the case of dutasteride it is an anilide linkage which might be broken less easily, biologically, relative to the aliphatic t-butyl group of finasteride for reasons other than steric factors.

I'm just speculating, mind.

 

[BaldingHelpMe]

Finasteride: tert-butyl

Dutasteride: [2,5-bis(trifluoromethyl)phenyl]

So if you take out the above part, they are identical in chemical names:
(1S,3aS,3bS,5aR,9aR,9bS,11aS)-N-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,5,5a,6,9b,10,11-dodecahydroindeno[5,4-f]quinoline-1-carboxamide

 

[BaldingHelpMe]

I'm just speculating, mind.

Could you also explain about half-life? So dutasteride stays in your blood for 5 weeks, while finasteride stays in blood for only 8 hours? That does not make sense since we're supposed to take dutasteride daily no matter the dosage.

 

[violetfluff]

Could you also explain about half-life? So dutasteride stays in your blood for 5 weeks, while finasteride stays in blood for only 8 hours? That does not make sense since we're supposed to take dutasteride daily no matter the dosage.

For dutasteride there appears to be at least two biological pathways to eliminate the substance from the body, the first one rapidly clears it with a half-life of 3-9days which occurs for low or acute exposure. Higher doses or more frequent doses are cleared more slowly with a half-life of 3-5 weeks so it appears the first pathway is of limited capacity.
So you have to maintain higher level of this compound to achieve this long half-life. The same might be true for finasteride but both pathway's half-life elimination times are considerably shorter.

 

[BaldingHelpMe]

So you have to maintain higher level of this compound to achieve this long half-life. The same might be true for finasteride but both pathway's half-life elimination times are considerably shorter.

So, they differ only in these two groups: [tert-butyl] for finasteride and [2,5-bis(trifluoromethyl)phenyl] for dutasteride. Just by looking at their two structures, do you see any reason the two drugs would interfere with each other? If I take both, finasteride and dutasteride, would dutasteride render both useless, so taking both would be like take none since finasteride and dutasteride compete with each other?

 

[violetfluff]

There is nothing to indicate that they will interfere with each other either chemically or pharmacologically.

As an irrelevant side note those two trifluoromethyl groups are often pharmacologically equivalent to bromine substituents so the bromine dutasteride analog (i.e. with a [2,5-bis(bromo)phenyl] group ) could have similar properties/activity as dutasteride.

 

[BaldingHelpMe]

As an irrelevant side note those two trifluoromethyl groups are often pharmacologically equivalent to bromine substituents so the bromine dutasteride analog (i.e. with a [2,5-bis(bromo)phenyl] group ) could have similar properties/activity as dutasteride.

Could you explain a little bit simpler in plain English? The two groups that are different are [tert-butyl] and [2,5-bis(trifluoromethyl)phenyl].

I've read that for some geno types, one would respond better with finasteride while some others respond better with dutasteride. I'm trying to understand why.

 

[violetfluff]

I was just speculating on a possible analog similar to dutasteride, it's not important.

I've read that for some geno types, one would respond better with finasteride while some others respond better with dutasteride. I'm trying to understand why.

That would have to do with some people, supposedly, having a variation in their 5aR enzymes where it might bond more weakly with either finasteride or dutasteride.
These compounds mimic testosterone in structure so that it fools the 5aR enzymes into accepting them but they get 'stuck' thus disabling the enzymes, a variation in the enzymes might not be able to fit the structure of finasteride but still fit dutasteride. This comes down to the shape of the molecule and its charge distribution fitting into the enzyme like a lock and key.

 

[BaldingHelpMe]

That would have to do with some people, supposedly, having a variation in their 5aR enzymes where it might bond more weakly with either finasteride or dutasteride.

So, normally people won't have a variation in their 5AR enzymes, this only happens to some people, right?

 

[violetfluff]

Yes, it's a minority.

 

[BaldingHelpMe]

Yes, it's a minority.

Could you explain a bit more about half-life? The gap between the half-life of these two drugs are huge, what does it mean if I take both? Since variation in 5AR enzymes are a minority, I assume I have normal 5AR enzymes, both finasteride and dutasteride are going to bind to the 5AR enzymes just fine, right? finasteride and dutasteride wouldn't attack each other, correct?

My goal is to eliminate as much 5AR enzymes as possible, which do you think is more effective, taking 2 pills of dutasteride + 1 pill of finasteride daily? Or just take 3 pills of dutasteride?

 

[violetfluff]

In chemistry/biochemistry a small change or 'bump' here or there on a molecule/drug can make a vast difference in how that it interacts with a person's biochemistry. Putting something as small as a methyl group somewhere could make a drug completely inactive or greatly change how the compound is metabolized. Even swapping a hydrogen atom out for deuterium can make a difference.

The two drugs wont interact directly with each other. Metabolism of them might overlap so taking dutasteride and finasteride together might extend the half-life of the finasteride or vice-vera due to one or both of the drugs saturating one or more of the metabolic pathways by which the body eliminates them.
But for these compounds serum half-life is not so important, the bottle-neck here is the slow regeneration rate of the of the 5aR enzymes. So even though finasteride has a short half-life of only a few hours its effects persist for a couple of weeks. When finasteride has bound to those enzymes it takes time to make more so you don't need to maintain a constant level of the drug to mop up reforming enzymes e.g. by longer half-life or spacing doses through-out the day.

If your 5aR enzymes are normal/common then finasteride is redundant if you are taking dutasteride, dutasteride will do everything and more than finasteride can do.
If you have an abnormality then one may be more effective than the other so if you don't know or are not patient to trial their effectiveness for you then you might want to take both just in case but of course there is a cost i.e. financial and possibly in terms of side effects too.
What doses you will need to take and of which drugs will depend on you, I can't say. You will have to suck it and see.

 

[BaldingHelpMe]

In chemistry/biochemistry a small change or 'bump' here or there on a molecule/drug can make a vast difference in how that it interacts with a person's biochemistry. Putting something as small as a methyl group somewhere could make a drug completely inactive or greatly change how the compound is metabolized. Even swapping a hydrogen atom out for deuterium can make a difference.

So, is it possible that taking both drugs could make them both inactive?

I had been a long time finasteride user, had been taking finasteride for over 12 years, then last year I added dutasteride and took both, I then had a massive shed and lost a lot of hair! Since then I had dropped finasteride and only take dutasteride now. Two possibilities, one is by taking dutasteride the first time, it caused me to have Telogen Effluvium. Second is, both drugs were interfering each other, rendering them both inactive, so it would be like I was taking none!

 

[violetfluff]

So, is it possible that taking both drugs could make them both inactive?

I had been a long time finasteride user, had been taking finasteride for over 12 years, then last year I added dutasteride and took both, I then had a massive shed and lost a lot of hair! Since then I had dropped finasteride and only take dutasteride now. Two possibilities, one is by taking dutasteride the first time, it caused me to have Telogen Effluvium. Second is, both drugs were interfering each other, rendering them both inactive, so it would be like I was taking none!

OK, I see.
They wont interact to render either ineffective, I my self am sensitive to Telogen Effluvium from dietary changes.

 

[BaldingHelpMe]

OK, I see.
They wont interact to render either ineffective, I my self am sensitive to Telogen Effluvium from dietary changes.

Did you recover from Telogen Effluvium? And how long did it take the hair lost from Telogen Effluvium to come back?

During that time I was also on a crash diet and lost almost 70 lbs! Could that cause me to have Telogen Effluvium?

 

[violetfluff]

Yeah absolutely! On one diet I was losing at about 7Kg (15lbs)/month and about 10 weeks after starting massive shedding began (worst I've ever had), it took 5-6 months of shedding for it to subside but it grew back i.e. visible density at the scalp started to fill in a couple of months after that. I stayed on the diet in-spite of the hair loss.
You hear of this being not uncommon for people who have undergone bariatric surgery or among anorexics.

But dutasteride is known by some on these boards for inducing some nasty sheds too as you've probably read.

 

[BaldingHelpMe]

For dutasteride there appears to be at least two biological pathways to eliminate the substance from the body, the first one rapidly clears it with a half-life of 3-9days which occurs for low or acute exposure. Higher doses or more frequent doses are cleared more slowly with a half-life of 3-5 weeks so it appears the first pathway is of limited capacity.
So you have to maintain higher level of this compound to achieve this long half-life. The same might be true for finasteride but both pathway's half-life elimination times are considerably shorter.

You're right. I found similar info on GSK's own study, saying for 0.1mg/day only has a half-life of about 3 days, and only higher dosage has a long half-life. Wow, I never knew that. Here is what I found:

"Pharmacokinetics. In this study, the pharmacokinetics of GI198745 have been described with a 2-compartment model with 2 parallel elimination pathways--a linear and a nonlinear pathway. At high concentrations the linear pathway dominates as the route of elimination, giving a clearance of of 0.58 L/h, which combined with the large volume of distribution (511 L) gives a terminal half-life of up to 5 weeks. As concentrations declined toward the concentration at which the saturable elimination pathway operates at half maximal rate (Km) (0.96 ng/mL), the proportion eliminated through the relatively rapid saturable elimination pathway increased, and the half-life decreased to about 3 days. This marked decrease in half-life was a consequence of the relatively high clearance (6.2 L/h) of the saturable pathway at low concentrations."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014202/

Question: So, let's say if I know I'll be out of town for a week and can't take dutasteride with me for that whole week; prior to the trip, if I've been taking 1.5mg for a week or so, the drug would still be in my bloodstream even I can't take it for a week?