Saturable binding of finasteride to steroid 5alpha-reductase as determinant of nonlinear pharmacokinetics

Drug Metab Pharmacokinet. 2010;25(2):208-13. doi: 10.2133/dmpk.25.208.

Abstract

Finasteride, a steroid 5alpha-reductase (5alphaR) inhibitor, is used to treat benign prostatic hyperplasia and androgenetic alopecia. We aimed to develop a pharmacokinetic/pharmacodynamic model to explain its nonlinear pharmacokinetics and describe the serum concentration profile of dihydrotestosterone (DHT) after finasteride administration. We developed a pharmacokinetic model incorporating a compartment that represents the binding of finasteride to 5alphaR. We fitted this model to the time-concentration profiles of finasteride after repeated administration of finasteride 0.2 and 1 mg/day. We constructed a pharmacodynamic model considering the inhibition of 5alphaR type I and type II (5alphaR1 and 5alphaR2). This model was fitted to the time profiles of serum DHT. The developed pharmacokinetic model well described nonlinear increase in AUC after repeated administration of finasteride. The association and dissociation rate constants were estimated to be 0.0293/nmol/hr and 0.0185/hr, respectively. Pharmacodynamic model analysis suggested that the 5alphaR1 inhibition is dose-dependent in the dose range from 0.2 to 100 mg, while the 5alphaR2 inhibition is almost saturated in the same dose range. Finasteride's saturable binding to 5alphaR2 is the likely cause of its nonlinear pharmacokinetics. The developed pharmacokinetic/pharmacodynamic model should allow prediction of plasma concentration profiles of finasteride and DHT.

MeSH terms

  • 5-alpha Reductase Inhibitors*
  • Animals
  • Dihydrotestosterone / blood*
  • Enzyme Inhibitors / pharmacokinetics*
  • Enzyme Inhibitors / pharmacology
  • Finasteride / pharmacokinetics*
  • Finasteride / pharmacology
  • Male
  • Nonlinear Dynamics
  • Prostatic Hyperplasia / blood
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / metabolism*
  • Rats

Substances

  • 5-alpha Reductase Inhibitors
  • Enzyme Inhibitors
  • Dihydrotestosterone
  • Finasteride