双氯芬酸在正常和完全弗氏佐剂诱导关节炎大鼠中的药代动力学-药效学模型。
Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats.
机构信息
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
出版信息
Acta Pharmacol Sin. 2012 Nov;33(11):1372-8. doi: 10.1038/aps.2012.67. Epub 2012 Jul 30.
AIM
To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E(2) (PGE(2)) as a biomarker.
METHODS
The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats. PGE(2) level in the rats was measured using an enzyme immunoassay. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibition of PGE(2) production. The inhibition of diclofenac on lipopolysaccharide (LPS)-induced PGE(2) production in blood cells was investigated in vitro.
RESULTS
Similar pharmacokinetic behavior of diclofenac was found both in normal and FCA-induced arthritic rats. Diclofenac significantly decreased the plasma levels of PGE(2) in both normal and arthritic rats. The inhibitory effect on PGE(2) levels in the plasma was in proportion to the plasma concentration of diclofenac. No delay in the onset of inhibition was observed, suggesting that the effect compartment was located in the central compartment. An inhibitory effect sigmoid I(max) model was selected to characterize the relationship between the plasma concentration of diclofenac and the inhibition of PGE(2) production in vivo. The I(max) model was also used to illustrate the inhibition of diclofenac on LPS-induced PGE(2) production in blood cells in vitro.
CONCLUSION
Arthritis induced by FCA does not alter the pharmacokinetic behaviors of diclofenac in rats, but the pharmacodynamics of diclofenac is slightly affected. A PK-PD model characterizing an inhibitory effect sigmoid I(max) can be used to fit the relationship between the plasma PGE(2) and diclofenac levels in both normal rats and FCA-induced arthritic rats.
目的
以前列腺素 E2（PGE2）作为生物标志物，描述在弗氏完全佐剂（FCA）诱导的关节炎大鼠中双氯芬酸的药代动力学-药效学模型。
方法
采用 20 日龄关节炎大鼠研究双氯芬酸的药代动力学。采用酶联免疫吸附试验测定大鼠体内 PGE2 水平。建立药代动力学-药效学（PK-PD）模型，阐明双氯芬酸血浆浓度与 PGE2 产生抑制之间的关系。研究了双氯芬酸在体外对脂多糖（LPS）诱导的血细胞 PGE2 产生的抑制作用。
结果
在正常和 FCA 诱导的关节炎大鼠中均发现双氯芬酸具有相似的药代动力学行为。双氯芬酸显著降低了正常和关节炎大鼠的血浆 PGE2 水平。对血浆中 PGE2 水平的抑制作用与双氯芬酸的血浆浓度成正比。未观察到抑制作用的起始延迟，表明效应室位于中央室。选择抑制效应 S 型 I（max）模型来描述双氯芬酸在体内与 PGE2 产生抑制之间的关系。该 I（max）模型还用于说明双氯芬酸对 LPS 诱导的血细胞中 PGE2 产生的抑制作用。
结论
FCA 诱导的关节炎不会改变双氯芬酸在大鼠中的药代动力学行为，但双氯芬酸的药效学略有影响。可使用具有抑制效应 S 型 I（max）的 PK-PD 模型来拟合正常大鼠和 FCA 诱导的关节炎大鼠中血浆 PGE2 与双氯芬酸水平之间的关系。
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