Ploeger B, Mensinga T, Sips A, Deerenberg C, Meulenbelt J, DeJongh J
Research Institute of Toxicology (RITOX), Utrecht, 3508 TD, The Netherlands.
Toxicol Appl Pharmacol. 2001 Jan 1;170(1):46-55. doi: 10.1006/taap.2000.9078.
Glycyrrhizic acid is widely applied as a sweetener in food products and chewing tobacco. Habitual consumption of this compound may lead to hypertension and electrolyte disturbances due to inhibition of 11-beta-hydroxysteroid dehydrogenase by the metabolite glycyrrhetic acid. The effect of 130 mg glycyrrhetic acid/day for 5 days on 11-beta-hydroxysteroid dehydrogenase activity was studied by measuring the cortisol-cortisone ratio in 24-h urine. A twofold increase in this ratio was observed. It took 4 days for the elevated urinary cortisol-cortisone ratio to return to the baseline ratio after cessation of the treatment. The pharmacokinetics of glycyrrhetic acid were studied after the first and last dose. Using data from a previously performed single-dose study and present multiple-dose treatment, a physiologically based pharmacokinetic model for glycyrrhetic acid was developed. The variability of the pharmacokinetics of glycyrrhetic acid in the population studied could be explained for a considerable part by interindividual differences in gastrointestinal transit of glycyrrhetic acid metabolites. The relationship between glycyrrhetic acid exposure and changes in urinary cortisol-cortisone ratio was described by a pharmacodynamic model, using nonlinear mixed-effect modeling. Literature data on the inhibitory effect of glycyrrhetic acid on 11-beta-hydroxysteroid dehydrogenase activity under various exposure scenarios could be adequately described by the model. Due to the relationship between the pharmacokinetics of glycyrrhetic acid and its inhibitory effect on 11-beta-hydroxysteroid dehydrogenase activity, reflected by a change in the urinary cortisol-cortisone ratio, this ratio might serve as a noninvasive marker to identify individuals at risk for glycyrrhizic acid over-consumption.
甘草次酸作为甜味剂广泛应用于食品和嚼烟中。长期食用该化合物可能会因代谢产物甘草次酸抑制11-β-羟基类固醇脱氢酶而导致高血压和电解质紊乱。通过测量24小时尿液中的皮质醇-可的松比值，研究了每天130毫克甘草次酸连续服用5天对11-β-羟基类固醇脱氢酶活性的影响。观察到该比值增加了两倍。治疗停止后，尿液中升高的皮质醇-可的松比值需要4天才能恢复到基线比值。在首次和末次给药后研究了甘草次酸的药代动力学。利用先前进行的单剂量研究数据和当前的多剂量治疗数据，建立了基于生理学的甘草次酸药代动力学模型。在所研究的人群中，甘草次酸药代动力学的变异性在很大程度上可以由甘草次酸代谢产物胃肠道转运的个体差异来解释。使用非线性混合效应模型，通过药效学模型描述了甘草次酸暴露与尿液皮质醇-可的松比值变化之间的关系。该模型可以充分描述文献中关于甘草次酸在各种暴露情况下对11-β-羟基类固醇脱氢酶活性抑制作用的数据。由于甘草次酸的药代动力学与其对11-β-羟基类固醇脱氢酶活性抑制作用之间的关系，通过尿液皮质醇-可的松比值的变化反映出来，该比值可能作为一种非侵入性标志物，用于识别甘草酸过量摄入风险个体。
