大鼠血浆中美托洛尔及其代谢物的立体选择性分析及其在氧化代谢中的应用。

Stereoselective analysis of metoprolol and its metabolites in rat plasma with application to oxidative metabolism.

作者信息

Boralli Vanessa Bergamin, Coelho Eduardo Barbosa, Cerqueira Paula Macedo, Lanchote Vera Lucia

机构信息

Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café s/n, Campus da USP, 14040-903 Ribeirão Preto, SP, Brazil.

出版信息

J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Sep 5;823(2):195-202. doi: 10.1016/j.jchromb.2005.06.038.

DOI:10.1016/j.jchromb.2005.06.038

PMID:16029965

Abstract

We investigated the stereoselective kinetic disposition and metabolism of metoprolol (MET) in rats. The racemic MET (15 mg/kg) was given by oral gavage and blood samples were collected from 0 to 10h (n=6 at each time point). The enantiomeric concentrations of MET and its metabolites alpha-hydroxymetoprolol (alpha-OHM) and O-demethylmetoprolol (ODM) were determined by HPLC using a Chiralpak AD chiral column and fluorescence detection. The pharmacokinetic parameters of unchanged MET and the formation of ODM did not show to be stereoselective. In contrast, the AUC (ng h/mL) of alpha-hydroxymetoprolol isomers were higher to I'R [638.2(525.2-706.2) for 1'R2R and 659.6(580.4-698.1) for 1'R,2S, mean, (95%CI)] than to I'S products [58.3(47.4-66.1) for 1'S,2R and 57.1(44.7-67.9) for 1'S,2S, mean, (95%CI)]. We conclude that the kinetic disposition of unchanged MET and the formation of ODM are not enantioselective in rats but the metabolism of alpha-OHM yields predominantly the 1'R-product.

摘要

我们研究了美托洛尔（MET）在大鼠体内的立体选择性动力学处置和代谢。外消旋美托洛尔（15mg/kg）经口灌胃给药，在0至10小时内采集血样（每个时间点n = 6）。使用Chiralpak AD手性柱和荧光检测的高效液相色谱法测定美托洛尔及其代谢产物α-羟基美托洛尔（α-OHM）和O-去甲基美托洛尔（ODM）的对映体浓度。未变化的美托洛尔的药代动力学参数和ODM的形成没有显示出立体选择性。相比之下，α-羟基美托洛尔异构体的AUC（ng h/mL）对于1'R产物[1'R,2R为638.2(525.2 - 706.2)，1'R,2S为659.6(580.4 - 698.1)，均值，(95%CI)]高于1'S产物[1'S,2R为58.3(47.4 - 66.1)，1'S,2S为57.1(44.7 - 67.9)，均值，(95%CI)]。我们得出结论，在大鼠中，未变化的美托洛尔的动力学处置和ODM的形成不是对映体选择性的，但α-OHM的代谢主要产生1'R产物。