Mechanism-based Pharmacokinetic-Pharmacodynamic Modeling of Bidirectional Effect of Danshensu on Plasma Homocysteine in Rats

Pharm Res. 2009 Aug;26(8):1863-73. doi: 10.1007/s11095-009-9899-x. Epub 2009 May 7.

Abstract

Purpose: To develop a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model to characterize and predict the bidirectional effect of danshensu on plasma total homocysteine (tHcy) in rats described in our previous paper.

Methods: The effect of danshensu on tHcy was assessed in rats after simultaneously methionine loading. Danshensu, its methylated metabolite and tHcy were all quantified after single intravenous injection of 20 mg/kg danshensu. The bidirectional effect, of which, elevated by danshensu methylation and decreased via transsulfuration promotion, was characterized by a PK-PD model, where direct stimulatory sigmoidal function and time-dependent transduction function were introduced for the two effects description, respectively.

Results: Modeling and simulations reveals that: (1) the elevated effect by methylation occurs before the decreased effect via transsulfuration promotion, and the decreased effect is more profoundly dose-dependent than the elevated effect; (2) two steps are simplified to describe the delayed stimulatory effect on the transsulfuration in the model; (3) long term administration of danshensu dose not affect tHcy in normal rats, while it significantly reduces tHcy in rats treated with methionine. This is in consistent with previous report.

Conclusions: The profiles were well-described by our PK-PD model, which constitutes a basis for the future development of mechanism-based model for polyphenols on Hcy in this paradigm.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Homocysteine / blood*
  • Lactates / pharmacokinetics*
  • Lactates / pharmacology*
  • Male
  • Models, Theoretical
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Lactates
  • Homocysteine
  • 3,4-dihydroxyphenyllactic acid