In vivo time-dependent inhibition of human steroid 5α-reductase by finasteride

• Published in: Journal of pharmaceutical sciences Vol. 85; no. 1; pp. 106 - 111
• Main Author: Tian, Gaochao
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01.01.1996; Wiley; American Pharmaceutical Association
• Subjects: 5-alpha Reductase Inhibitors; Biological and medical sciences; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Finasteride - pharmacokinetics; Finasteride - pharmacology; Genital system. Reproduction; Humans; Mathematical Computing; Medical sciences; Models, Biological; Pharmacology. Drug treatments; Human; In vivo; Dihydrotestosterone; Enzyme; Enzyme inhibitor; Models; Oxidoreductases; Azasteroid; Biological activity
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1021/js950100g

Finasteride (17β‐(N‐t‐butylcarbamoyl)‐4‐aza‐5α‐androstan‐1‐en‐3‐one), a time‐dependent, irreversible inhibitor of human steroid 5R‐reductase (5AR), may only reduce dihydrotestosterone levels in humans by ∼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.