IN-VIVO TIME-DEPENDENT INHIBITION OF HUMAN STEROID 5-ALPHA-REDUCTASE BY FINASTERIDE

Finasteride (17 beta-(N-t-butylcarbamoyl)-4-aza-5 alpha-androstan-1-en -3-one), a time-dependent, irreversible inhibitor of human steroid 5 a lpha-reductase (5AR), may only reduce dihydrotestosterone levels in hu mans by similar to 60% at the doses used clinically. A theoretical mod el was developed to aid in understanding the in vivo efficacy data of finasteride. According to the theory, whether an enzyme can be inhibit ed in vivo by an irreversible inhibitor is dependent on the value of a ratio of the observed rate of enzyme inhibition over the rate constan t for inhibitor elimination. As shown, this ratio should be in excess of 3 for >95% inhibition of the target in vivo. Subsequent application of the theory to evaluate the in vivo efficacy data of finasteride in dicates low effective concentration of finasteride at the inhibition s ites and suggests complete inhibition of 5AR 2, but insufficient suppr ession of 5AR 1 at the clinical doses.