沙格列汀及其活性代谢物 5-羟基沙格列汀在 2 型糖尿病大鼠中的药代动力学/药效学模型。

IF 2.8 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Tianyan Wang, Ting Tao, Yi Liu, Jie Dong, Shanhong Ni, Yun Liu, Yanli Li, Ning Xu, Zengxian Sun
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引用次数: 0

摘要

背景和目的:目前尚不清楚体内的沙格列汀母体(SAX)是否与体外的沙格列汀母体相同,体外的沙格列汀母体是5-羟基沙格列汀母体(5-OH SAX)的两倍。本研究旨在构建药代动力学-药效学(PK-PD)关联模型,以评估体内母体沙格列汀浓度与疗效之间的真实关系:首先,我们建立了可靠的超高效液相色谱-质谱联用(UPLC-MS/MS)方法和DPP-4抑制比测定方法。然后,将 T2DM 大鼠随机分为四组,分别为静脉注射 5-OH SAX(0.5 mg/kg)组和生理盐水组、胃内注射 SAX(10 mg/kg)组和羧甲基纤维素钠(CMC-Na)组。在不同的时间点采集血浆样本进行后续检测。最后,我们利用测得的浓度和抑制比构建了5-OH SAX和母体SAX的PK-PD联系模型:结果:两室加和模型显示了SAX和5-OH SAX的药代动力学过程,SAX和5-OH SAX的浓度-效应关系分别用西格玛Emax模型和西格玛Emax加E0模型来表示。拟合参数显示,SAX 给药后吸收迅速(Tmax=0.11 h,t1/2,ka=0.07 h),在体内分布广泛(V ≈ 20 L/kg),血浆暴露量达到 3282.06 ng*h/mL,消除半衰期为 6.13 h。根据最终拟合参数EC50,EC50,5-OH SAX=0.46EC50,SAX(母体),认为5-OH SAX的抑制作用约为母体SAX的一半,这与文献报道一致:本研究建立的母体SAX的PK-PD联系模型可以根据非临床数据预测其在T2DM大鼠体内的药代动力学过程以及对DPP-4的抑制作用强度。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pharmacokinetic/Pharmacodynamic modelling of Saxagliptin and its active metabolite, 5-hydroxy Saxagliptin in rats with Type 2 Diabetes Mellitus.

Background and purposes: It is unclear whether the parent Saxagliptin (SAX) in vivo is the same as that in vitro, which is twice that of 5-hydroxy Saxagliptin (5-OH SAX). This study is to construct a Pharmacokinetic-Pharmacodynamic (PK-PD) link model to evaluate the genuine relationship between the concentration of parent SAX in vivo and the effect.

Methods: First, we established a reliable Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS) method and DPP-4 inhibition ratio determination method. Then, the T2DM rats were randomly divided into four groups, intravenous injection of 5-OH SAX (0.5 mg/kg) and saline group, intragastric administration of SAX (10 mg/kg) and Sodium carboxymethyl cellulose (CMC-Na) group. Plasma samples were collected at different time points for subsequent testing. Finally, we used the measured concentrations and inhibition ratios to construct a PK-PD link model for 5-OH SAX and parent SAX.

Results: A two-compartment with additive model showed the pharmacokinetic process of SAX and 5-OH SAX, the concentration-effect relationship was represented by a sigmoidal Emax model and sigmoidal Emax with E0 model for SAX and 5-OH SAX, respectively. Fitting parameters showed SAX was rapidly absorbed after administration (Tmax=0.11 h, t1/2, ka=0.07 h), widely distributed in the body (V ≈ 20 L/kg), plasma exposure reached 3282.06 ng*h/mL, and the elimination half-life was 6.13 h. The maximum plasma dipeptidyl peptidase IV (DPP-4) inhibition ratio of parent SAX was 71.47%. According to the final fitting parameter EC50, EC50, 5-OH SAX=0.46EC50, SAX(parent), it was believed that the inhibitory effect of 5-OH SAX was about half of the parent SAX, which is consistent with the literature.

Conclusions: The PK-PD link model of the parent SAX established in this study can predict its pharmacokinetic process in T2DM rats and the strength of the inhibitory effect of DPP-4 based on non-clinical data.

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来源期刊
BMC Pharmacology & Toxicology
BMC Pharmacology & Toxicology PHARMACOLOGY & PHARMACYTOXICOLOGY&nb-TOXICOLOGY
CiteScore
4.80
自引率
0.00%
发文量
87
审稿时长
12 weeks
期刊介绍: BMC Pharmacology and Toxicology is an open access, peer-reviewed journal that considers articles on all aspects of chemically defined therapeutic and toxic agents. The journal welcomes submissions from all fields of experimental and clinical pharmacology including clinical trials and toxicology.
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