大鼠体内甲基橙连续脱甲基和胆汁分泌的药代动力学模型。

Pharmacokinetic model for the successive demethylation and biliary secretion of methyl orange in the rat.

O'Reilly W J, Pitt P A, Ryan A J

Br J Pharmacol. 1971 Sep;43(1):167-79. doi: 10.1111/j.1476-5381.1971.tb07166.x.

Abstract

A one-compartment pharmacokinetic model was developed in which a drug underwent two successive metabolical reactions (for example, metabolism followed by conjugation) and free drug and both metabolites were excreted.2. Techniques were described whereby graphical estimates of the first-order rate constants may be derived from cumulative excretion data on the drug and its metabolites. Computer simulation techniques were used to show that the experimental data permit reasonably accurate estimation of the rate constants of the model by graphical and computer methods.3. Tritiated methyl orange (2 mg) was administered to five groups of six rats with biliary cannulation. The bile produced by each animal was collected at hourly intervals for 6 h and the amounts of methyl orange and its metabolites, 4'sulpho-4-methylaminoazobenzene and 4'sulpho-4-aminoazobenzene, determined by thin layer chromatography and radioactive counting techniques.4. The data were analysed graphically and with an iterative digital computer programme to yield the first-order rate constants for the successive demethylation steps in the metabolism of methyl orange. The removal of the first methyl group had a rate constant of 0.684+/-0.142 h(-1) (+/-S.D.) and the second methyl group 1.00+/-0.302 h(-1). The rate constant for biliary excretion of the free methyl orange was 0.164+/-0.042 h(-1), for the monomethyl derivative 0.672+/-0.461 h(-1), and for the demethylated metabolite 6.413+/-3.222 h(-1).

摘要

建立了一个一室药代动力学模型，其中一种药物经历两个连续的代谢反应（例如，先代谢后结合），游离药物及其两种代谢产物均被排泄。
描述了一些技术，通过这些技术可以从药物及其代谢产物的累积排泄数据中得出一级速率常数的图形估计值。使用计算机模拟技术表明，实验数据允许通过图形法和计算机方法对模型的速率常数进行合理准确的估计。
给五组每组六只胆管插管的大鼠注射2毫克的氚标记甲基橙。每只动物每小时收集一次胆汁，共收集6小时，并通过薄层色谱法和放射性计数技术测定甲基橙及其代谢产物4'-磺基-4-甲基氨基偶氮苯和4'-磺基-4-氨基偶氮苯的量。
对数据进行图形分析，并使用迭代数字计算机程序得出甲基橙代谢过程中连续脱甲基步骤的一级速率常数。第一个甲基的去除速率常数为0.684±0.142 h⁻¹（±标准差），第二个甲基为1.00±0.302 h⁻¹。游离甲基橙的胆汁排泄速率常数为0.164±0.042 h⁻¹，单甲基衍生物为0.672±0.461 h⁻¹，脱甲基代谢产物为6.413±3.222 h⁻¹。