PROPECIAHELP: Persistent Finasteride Propecia Proscar side effects info & discussion forum

Sex Hormones (Male): Analogs and Antagonists

http://www.wiley-vch.de/books/sample/3527306501_c01.pdf

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Page 44:

Finasteride
Chemical Class: Androstane


Page 49-50:

... The most extensively studied class of 5α-reductase inhibitors is the 4-azasteroids, which includes the drug finasteride (Proscar). Finasteride is the first 5α-reductase inhibitor approved in the United States for the treatment of BPH.

This drug has approximately a 100-fold greater affinity for type 2 5α-reductase than for the type 1 enzyme, demonstrating an IC50 value of 4.2 nM for type 2 5α-reductase. In humans, finasteride decreases prostatic DHT levels by 70 to 90% and reduces prostate size, while testosterone tissue levels increased.

... These agents were originally designed to mimic the putative 3-enolate intermediate of testosterone and serve as transition-state inhibitors. Subsequently, finasteride was shown to produce time-dependent enzyme inactivation and function as a mechanism-based inactivator.

Futher proof that Finasteride is a STEROID compound.

http://www.nlm.nih.gov/cgi/mesh/2008/MB ... w=expanded

Scroll down to see for yourself.

Furthermore...

http://books.google.ca/books?hl=en&lr=& ... #PPA112,M1

More...

http://www.andrologyjournal.org/cgi/reprint/15/4/298

From: http://books.google.com/books?ct=result ... #PPA206,M1

Interesting that dialysis restores enzyme activity.

Inactivation of enzyme is only for those enzymes that have been bound by Finasteride... but of course, testing for 5AR2 enzyme activity after Finasteride use would probably give us definite yes or no answers as to wether our bodies re-synthesized 5AR2 or not.

Note: Mechanism-based inhibition = suicide inhibitor

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http://www.simcyp.com/ResearchDevelopme ... echenzyme/

"Mechanism (or time) -based enzyme inhibition is associated with irreversible or quasi-irreversible loss of enzyme function, requiring synthesis of new enzyme before activity is restored.

The consequences of mechanism-based inhibition are:

- auto-inhibition of the clearance of the inactivator itself
- prolonged inhibition of the clearance of other drugs that share the same enzyme.

There may also be serious immunotoxicological consequences if a reactive intermediate is covalently bound to the enzyme. Therefore, screening of new compounds for mechanism-based enzyme inhibition is now standard practice within the pharmaceutical industry"

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http://lib.bioinfo.pl/pmid:9749833

Cloning, expression and characterization of rhesus macaque types 1 and 2 5alpha-reductase: evidence for mechanism-based inhibition by finasteride.


The rhesus macaque types 1 and 2 5alpha-reductase (5aR1 and 5aR2) were cloned and expressed in COS cells to facilitate comparison of rhesus and human 5aRs. The deduced protein sequences of the rhesus SaRs shared 94% and 96% identity with the human type 1 and 2 isozymes, respectively.

Despite a four amino acid insertion at the N-terminal region of rhesus 5aR1, the biochemical properties of rhesus and human homologs are very similar with respect to pH optimum, Km values for testosterone and progesterone, and inhibition by a variety of inhibitors.

As expected, the biochemical properties of the human and rhesus 5aR2 are also very similar. The mechanism of inhibition of the rhesus 5aR1 and 5aR2 by finasteride was investigated in more detail.

Finasteride displays time dependent inhibition of the rhesus 5aR1 and 5aR2 with second order rate constants of 4 x 10(3) M(-1) s(-1) and 5.2 x 10(5) M(-1)s(-1). Inhibition of rhesus 5aR2 with 3H-finasteride resulted in 3H bound to the enzyme which is not released by dialysis.

Heat denaturation of the [rhesus SaR2:inhibitor] complex releases dihydrofinasteride, a breakdown product presumably related to the NADP+-adduct previously identified with the human SaRs (Bull et al., Mechanism-based inhibition of human steroid 5alpha-reductase by finasteride: Enzyme catalyzed formation of NADP-dihydrofinasteride, a potent bisubstrate analog inhibitor. J. Amer. Chem. Soc., 1996, 118, 2359-2365).

Taken together, these results provide good evidence that the rhesus macaque is a suitable model to evaluate the pharmacological properties of finasteride and other 5aR inhibitors.


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Attached image from:

http://books.google.ca/books?id=7JrFamz ... #PPA109,M1

Chemical Mechanism of the Covalent Modification of 5a-Reductases by Finasteride As Probed by Secondary Tritium Isotope Effects

http://pubs.acs.org/cgi-bin/abstract.cg ... 13a034.pdf

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And so even if finasteride unbinds slowly from the 5AR enzymes that it attaches to, it "deactivates" said enzymes?? What the hell!? i'm assuming more 5AR enzymes are created albeit slowly in the prostate over time...?

If you look at the above post (text in orange and screenshot)...

http://www.propeciahelp.com/forum/viewt ... =9473#9473

... it says synthesis of new enzyme is required for activity to be restored.

Since nobody here has actually been tested (genital skin fibroblast culture, Adiol-G bloodtest) to see if in fact 5AR2 enzymes have been "re-synthesized" by the body post-Fin and thus activity restored, it's still a theory worth investigating.

Although, some guys have high levels of DHT post-Fin... but perhaps 5AR1 is contributing to these values (see screenshots).

http://www.propeciahelp.com/forum/viewt ... =5838#5838

http://www.propeciahelp.com/forum/viewt ... =4881#4881

STUDENT QUESTION

Dear Dr Billack:
I am confused about how finasteride can block the activity of 5-alpha reductase. Is it a competitive inhibitor?

Reply: The topic is understandably confusing. The drug is actually what is known as a 'mechanism-based inhibitor.' Recall that the definition of a mechanism-based inhibitor is, "a competitive inhibitor that is converted to an irreversible inhibitor at the active site of the enzyme." So, the answer to the question really is "first competitive and then irreversible"

Let's first look at it this way. Finasteride COMPETES with testosterone for binding to the 5-alpha reductase enzyme. Once finasteride is in the active site, the enzyme starts to work on it, as if it were working on testosterone. In the process, the finasteride gets converted to a reactive product which then irreversibly binds to the enzyme-NADP cofactor complex and, in essence, inactivates the enzyme from making DHT. Note that the half-life of the enzyme-NADP-inhibitor complex which is formed is about 1 month.
The original article describing this process can be found at http://pubs.acs.org/subscribe/journals/ ... 3069t.html

For the purpose of my portion of the course, I will group drugs such as finasteride and dutasteride into the general class of "5-alpha reductase inhibitors" and will not focus on the details of the chemistry responsible for the inhibition.


So now at least we know that finasteride is only binding to the enzym instead of killing it. I would rather guess our problem sound not to be hormonal.

Found on the: http://pharmakologika.blogspot.com/

Dutasteride is also a competitive inhibitor. It means that 5 alpha reductase is still there. Dutasteride & Finasteride are not destroying enzyms, they both bind to the molecule.

Dutasteride & Finasteride Mechanisms of Action
Dutasteride and finasteride are both 5-alpha-reductase (5AR) inhibitors. Both treatments work by inhibiting 5AR, the enzyme responsible for converting testosterone to dihydrotestosterone (DHT). DHT is the primary androgen in the prostate. It is a primary factor in the development and progression of benign prostatic hyperplasia (BPH) and other prostate diseases and is also a major cause of hair loss.

Dutasteride is a competitive inhibitor of both type-1 and type-2 isoenzymes of DHT, with 45-fold greater potency than finasteride against type-1 and type-2 isoenzymes. Approximately 85% to 90% of DHT is suppressed by the inhibition of type-2 isozymes. The remaining DHT is hypothesized to be from type-1 5-alpha-reductase. Finasteride is a competitive inhibitor of 5-alpha-reductase that selectively inhibits the type-2 isoenzyme. The dual inhibition resulting from dutasteride treatment may be beneficial in prostatic diseases that depend on androgens, as both isoenzymes are up-regulated in BPH while only the type-1 isoenzyme is up-regulated in prostate cancer. It is not yet known if there are clinical differences between selective inhibitors and dual inhibitors of 5-alpha-reductase in the treatment of BPH.

http://www.dutasteride.com/articles/dut ... eride.html

Fin binds so tightly to the enzyme it is essentially irreversible for those enzymes that have been bound. This has been discussed before on here, as noted in all the materials posted above.

Just to be clear: those enzymes bound by Fin NEVER REGAIN ACTIVITY after Fin -- only new 5AR2 that is re-synthesized by the patient can restore 5AR2 activity.

It is likely the 5AR2 enzymes that have been bound are in effect destroyed, considering the below.

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MECHANISM-BASED INHIBITION OF HUMAN STEROID 5-ALPHA-REDUCTASE BY FINASTERIDE - ENZYME-CATALYZED FORMATION OF NADP-DIHYDROFINASTERIDE, A POTENT BISUBSTRATE ANALOG INHIBITOR
http://d.wanfangdata.com.cn/NSTLQK_NSTL_QK10273492.aspx

Finasteride is processed with a second-order rate constant, ki/Ki = 1 × 106 M-1 s-1, that approaches kcat/Km for reduction of testosterone, 3 × 106 M-1 s-1, and essentially every catalytic event is lethal (partition ratio ≤ 1.07).


Irreversible inhibition of human 5α-reductase
http://www.freepatentsonline.com/5962442.html

The method of the present invention provides for sustained inhibition of 5α-reductase even when the dose regimen is interrupted and the levels of the 3-oxo-4-azasteroid drug having a 1,2-double bond drop, as when the patient misses a dose. In this situation of interrupted dosing, 5α-reductase that had been inhibited cannot recover from the inhibition and additional drug is required to inhibit only the 5α-reductase that has been newly synthesized by the patient.


The formation (k 2 ) and turnover (k 4 ) of the high-affinity enzyme-inhibitor complex appear to be essentially irreversible. In practice, the halflife of the enzyme-inhibitor complex is so long that the inhibition is for all intents irreversible, and release of the inhibitor probably occurs by death of the enzyme rather than turnover to regenerate catalytically competent enzyme.

When you say the half life of the enzyme unbinding from finasteride is so long it's essentially irreversible, is not the half life 30 days? 30 days does not seem like a long time at all!

http://books.google.ca/books?id=l2rMy8Q ... ch_s&cad=0

http://books.google.ca/books?id=l2rMy8Q ... #PPA226,M1