Yuancheng Chen1, Yanguang Cao, Jia Zhou, Xiaoquan Liu. 1. Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing City, 210009, People's Republic of China.
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.
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.