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 alpha-reductase (5AR), may only reduce dihydrotestosterone levels in humans by approximately 60% at the doses used clinically. A theoretical model was developed to aid in understanding the in vivo efficacy data of finasteride. According to the theory, whether an enzyme can be inhibited in vivo by an irreversible inhibitor is dependent on the value of a ratio of the observed rate of enzyme inhibition over the rate constant 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 indicates low effective concentration of finasteride at the inhibition sites and suggests complete inhibition of 5AR 2, but insufficient suppression of 5AR 1 at the clinical doses.