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

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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.

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Abbreviations

A c :

amount of danshensu in central compartment (A c,0, initial value)

A m :

amount of methylated metabolite of danshensu (A m,0, initial value)

A p :

amount of danshensu in peripheral compartment (A p,0, initial value)

C :

concentration of danshensu in central compartment

C m :

concentration of methylated metabolite of danshensu

COMT:

catechol-O-methyltransferase

DSS:

danshensu

D T :

changed value of T 2 level

f DSS_kp :

transfer function describing the stimulation of danshensu (C) on k p

f DSS_kt :

transfer function describing the induction of danshensu (C) on the transduction pathway (k t)

f T_kr :

transfer function characterizing the promotion of transit compartment T 2 on k r

Hcy:

homocysteine

k 0 :

zero-order rate constant of methionine production

k 12 :

first-order rate constant of danshensu from central to peripheral compartment

k 21 :

first-order rate constant of danshensu from peripheral to central compartment

k e :

first-order rate constant of danshensu elimination from central compartment

k em :

first-order rate constant of elimination of the metabolite

k m :

first-order rate constant of methylation process

k p :

first-order rate constant of transformation from methionine to Hcy

k r :

first-order rate constant of Hcy elimination

k t :

turnover rate constant of transduction

Met:

methionine

Met-Loading rats:

a general term for (−,M) rats and (D,M) rats

n DSS_kp :

Hill coefficient for danshensu stimulation on Hcy

n Met :

ratio between P 0′ and P 0 in Met-Loading rats

Normal rats:

a general term for (−,−) rats and (D,−) rats

P :

plasma concentration of methionine (P 0 and P 0′, initial concentration in normal rats and Met-Loading rats, respectively)

PD:

pharmacodynamics

PK:

pharmacokinetics

R :

plasma concentration of tHcy (R 0, initial concentration)

SAM:

S-adenosylmethionine

SC50_DSS_kp :

concentration of danshensu producing 50% of S max_DSS_kp

SC50_DSS_kt :

concentration of danshensu producing 50% S max_DSS_kt

S max_DSS_kp :

capacity factor for danshensu stimulation on Hcy

S max_DSS_kt :

capacity factor for danshensu stimulation on k t

S max_T_kr :

capacity factor for transduction-induced stimulation on k r

T 1 and T 2 :

first and second transduction compartment (T 1,0 and T 2,0, initial values)

T 50 :

D T level producing 50% of S max_T_kr

tHcy:

total homocysteine

SAH:

S-adenosyl-l-homocysteine

V d :

apparent distribution volume of danshensu and the metabolite

V d,Met :

apparent distribution volume of methionine

(−,−) group:

rats with normal saline

(D,−) group:

rats with danshensu

(−,M) group:

rats with methionine loading

(D,M) group:

rats with both methionine and danshensu

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Acknowledgments

We would like to thank Xiao-Jia Wang, Yue-Miao Yin, Chun-Hua Xu, Ping Wang for technical help with animal and bioanalytical aspects of the studies. This research was supported by the National Natural Science Foundation of the People’s Republic of China (No. 30772609).

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Authors and Affiliations

  1. Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing City, 210009, People’s Republic of China

    Yuancheng Chen, Yanguang Cao, Jia Zhou & Xiaoquan Liu

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  1. Yuancheng Chen
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  2. Yanguang Cao
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  3. Jia Zhou
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  4. Xiaoquan Liu
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Corresponding author

Correspondence to Xiaoquan Liu.

Additional information

Yuancheng Chen, Yanguang Cao contributed equally to this work.

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Chen, Y., Cao, Y., Zhou, J. et al. Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of Bidirectional Effect of Danshensu on Plasma Homocysteine in Rats. Pharm Res 26, 1863–1873 (2009). https://doi.org/10.1007/s11095-009-9899-x

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