A model for the turnover of dihydrotestosterone in the presence of the irreversible 5 alpha-reductase inhibitors GI198745 and finasteride

Clin Pharmacol Ther. 1998 Dec;64(6):636-47. doi: 10.1016/S0009-9236(98)90054-6.


Objective: To develop a pharmacokinetic-pharmacodynamic model that characterizes the conversion of testosterone to dihydrotestosterone (DHT) by 5 alpha-reductase types 1 and 2 and the irreversible inhibition of 5 alpha-reductase by finasteride, a 5 alpha-reductase type 2 inhibitor and by GI198745 (dutasteride), a potent and specific dual 5 alpha-reductase inhibitor.

Methods: Healthy men (n = 48) received doses of 0.1 to 40 mg GI198745 (n = 4 subjects per dose), 5 mg finasteride (n = 8), or placebo (n = 8) in a parallel-group study. Plasma concentrations of GI198745, finasteride, and DHT were measured frequently up to 8 weeks after dosing. Models were fitted with mixed-effects modeling with the NONMEM program.

Results: The pharmacodynamics were well described with a model that accounted for the rates of DHT formation and elimination, 5 alpha-reductase turnover, relative capacity of the 2 5 alpha-reductase isozymes, and the rates of irreversible inhibition of one (finasteride) or both (GI198745) types of 5 alpha-reductase. The model indicated that type 2 5 alpha-reductase contributed approximately 80% of plasma DHT. GI198745 was about 3-fold more potent than finasteride on 5 alpha-reductase type 2. Nearly full blockade of both isozymes was achieved at doses of 10 mg or more GI198745, although the potency of this agent on 5 alpha-reductase type 1 was less than on type 2.

Conclusions: A physiologically based model for the turnover and irreversible inhibition of 5 alpha-reductase and for formation and elimination of DHT described the data well. This model helps explain differences in the rates of onset and offset of effect and offers a way to determine the relative potency of the irreversible 5 alpha-reductase inhibitors.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • 5-alpha Reductase Inhibitors*
  • Adult
  • Azasteroids / pharmacology*
  • Dihydrotestosterone / metabolism*
  • Dutasteride
  • Enzyme Inhibitors / pharmacology*
  • Finasteride / pharmacology*
  • Humans
  • Male
  • Middle Aged
  • Reference Values
  • Single-Blind Method
  • Testosterone / metabolism


  • 5-alpha Reductase Inhibitors
  • Azasteroids
  • Enzyme Inhibitors
  • Dihydrotestosterone
  • Testosterone
  • Finasteride
  • Dutasteride