Mechanism-based pharmacokinetic-pharmacodynamic modeling of bidirectional effect of danshensu on plasma homocysteine in rats.
OBJECTIVE
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.
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing City, 210009, People's Republic of China.
Yuancheng
Y
Chen
Yanguang
Y
Cao
Jia
J
Zhou
Xiaoquan
X
Liu
D000818:Animals; D006710:Homocysteine / Q000097:blood*; D007773:Lactates / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008962:Models, Theoretical; D051381:Rats; D017207:Rats, Sprague-Dawley
D007773:Lactates; D006710:Homocysteine; C035055:3,4-dihydroxyphenyllactic acid