2 型糖尿病大鼠中西格列汀及其活性代谢物 5-羟基西格列汀的药代动力学/药效学模型建立。

Pharmacokinetic/Pharmacodynamic modelling of Saxagliptin and its active metabolite, 5-hydroxy Saxagliptin in rats with Type 2 Diabetes Mellitus.

机构信息

Department of Pharmacy, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, 222061, China.

Endocrinology Department, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, 222061, China.

出版信息

BMC Pharmacol Toxicol. 2024 Jun 26;25(1):35. doi: 10.1186/s40360-024-00757-3.

DOI:10.1186/s40360-024-00757-3

PMID:39103956

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11299271/

Abstract

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 E model and sigmoidal E with E model for SAX and 5-OH SAX, respectively. Fitting parameters showed SAX was rapidly absorbed after administration (T=0.11 h, t=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 EC, EC=0.46EC, 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.

摘要

背景与目的

尚不清楚体内的母体沙格列汀（SAX）是否与体外的 SAX 相同，后者是 5-羟基沙格列汀（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 SAX 浓度与疗效之间的真实关系。

方法

首先，我们建立了一种可靠的超高效液相色谱-质谱联用（UPLC-MS/MS）方法和 DPP-4 抑制率测定方法。然后，将 T2DM 大鼠随机分为 4 组，静脉注射 5-OH SAX（0.5mg/kg）和生理盐水组，灌胃给予 SAX（10mg/kg）和羧甲基纤维素钠（CMC-Na）组。在不同时间点采集血浆样本进行后续检测。最后，我们使用测量浓度和抑制率构建 5-OH SAX 和母体 SAX 的 PK-PD 关联模型。

结果

一个具有附加模型的两室模型显示了 SAX 和 5-OH SAX 的药代动力学过程，浓度-效应关系分别由 SAX 和 5-OH SAX 的 sigmoidal E 模型和 sigmoidal E 与 E 模型表示。拟合参数表明，SAX 给药后迅速吸收（T=0.11h，t=0.07h），广泛分布于体内（V≈20L/kg），血浆暴露量达到 3282.06ng*h/mL，消除半衰期为 6.13h。母体 SAX 的最大血浆二肽基肽酶 IV（DPP-4）抑制率为 71.47%。根据最终拟合参数 EC，EC=0.46EC，认为 5-OH SAX 的抑制作用约为母体 SAX 的一半，与文献一致。