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Related Experiment Videos

Finasteride: a slow-binding 5 alpha-reductase inhibitor

B Faller1, D Farley, H Nick

  • 1Pharma Research Division, Ciba-Geigy Ltd., Basel, Switzerland.

Biochemistry
|June 1, 1993
PubMed
Summary

Finasteride binding to 5 alpha-reductase is slower than previously thought, forming a stable enzyme-inhibitor complex. This interaction has a lower dissociation constant, indicating a stronger, longer-lasting effect than earlier studies suggested.

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Area of Science:

  • Biochemistry
  • Pharmacology

Background:

  • Steroid 5 alpha-reductase is a key enzyme in androgen metabolism.
  • Finasteride is a known inhibitor of 5 alpha-reductase, used clinically.
  • Previous studies assumed rapid, reversible binding of finasteride to the enzyme.

Purpose of the Study:

  • To investigate the kinetics of finasteride's interaction with human prostatic 5 alpha-reductase.
  • To determine the association and dissociation rates of the enzyme-inhibitor complex.
  • To re-evaluate the binding affinity of finasteride to 5 alpha-reductase.

Main Methods:

  • Enzyme kinetics study using a human prostatic microsomal preparation.
  • Measurement of enzyme-inhibitor complex formation over time.
  • Determination of rate constants (kon) and equilibrium dissociation constants (Ki* and Ki).

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Main Results:

  • Enzyme-inhibitor complex formation is not instantaneous, with a slow association rate constant (kon = 2.7 x 10(5) M-1 s-1).
  • The high activation energy (150 kJ mol-1) suggests a non-diffusion-controlled association process, possibly involving intermediate steps.
  • The overall equilibrium dissociation constant (Ki) is significantly lower than previously reported (<< 10(-9) M), indicating a very tight and stable binding.

Conclusions:

  • Finasteride's interaction with 5 alpha-reductase is characterized by slow association kinetics.
  • The tight binding (low Ki) suggests a prolonged inhibitory effect.
  • These findings refine our understanding of finasteride's mechanism of action at the molecular level.