Siebert Gerhard A, Hung Daniel Y, Chang Ping, Roberts Michael S
Department of Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia.
J Pharmacol Exp Ther. 2004 Jan;308(1):228-35. doi: 10.1124/jpet.103.056770. Epub 2003 Oct 17.
This study investigated the relative contribution of ion-trapping, microsomal binding, and distribution of unbound drug as determinants in the hepatic retention of basic drugs in the isolated perfused rat liver. The ionophore monensin was used to abolish the vesicular proton gradient and thus allow an estimation of ion-trapping by acidic hepatic vesicles of cationic drugs. In vitro microsomal studies were used to independently estimate microsomal binding and metabolism. Hepatic vesicular ion-trapping, intrinsic elimination clearance, permeability-surface area product, and intracellular binding were derived using a physiologically based pharmacokinetic model. Modeling showed that the ion-trapping was significantly lower after monensin treatment for atenolol and propranolol, but not for antipyrine. However, no changes induced by monensin treatment were observed in intrinsic clearance, permeability, or binding for the three model drugs. Monensin did not affect binding or metabolic activity in vitro for the drugs. The observed ion-trapping was similar to theoretical values estimated using the pHs and fractional volumes of the acidic vesicles and the pKa values of drugs. Lipophilicity and pKa determined hepatic drug retention: a drug with low pKa and low lipophilicity (e.g., antipyrine) distributes as unbound drug, a drug with high pKa and low lipophilicity (e.g., atenolol) by ion-trapping, and a drug with a high pKa and high lipophilicity (e.g., propranolol) is retained by ion-trapping and intracellular binding. In conclusion, monensin inhibits the ion-trapping of high pKa basic drugs, leading to a reduction in hepatic retention but with no effect on hepatic drug extraction.
本研究调查了离子捕获、微粒体结合以及游离药物分布作为决定因素在离体灌注大鼠肝脏中碱性药物肝内滞留方面的相对贡献。离子载体莫能菌素用于消除囊泡质子梯度，从而能够估计阳离子药物在酸性肝囊泡中的离子捕获情况。体外微粒体研究用于独立估计微粒体结合和代谢情况。使用基于生理的药代动力学模型得出肝囊泡离子捕获、内在消除清除率、通透表面积乘积和细胞内结合情况。模型显示，莫能菌素处理后，阿替洛尔和普萘洛尔的离子捕获显著降低，但安替比林未出现此情况。然而，对于这三种模型药物，未观察到莫能菌素处理引起的内在清除率、通透性或结合方面的变化。莫能菌素在体外对这些药物的结合或代谢活性没有影响。观察到的离子捕获与使用酸性囊泡的pH值、分数体积以及药物的pKa值估计的理论值相似。脂溶性和pKa决定肝内药物滞留：pKa低且脂溶性低的药物（如安替比林）以游离药物形式分布，pKa高且脂溶性低的药物（如阿替洛尔）通过离子捕获分布，pKa高且脂溶性高的药物（如普萘洛尔）通过离子捕获和细胞内结合而滞留。总之，莫能菌素抑制高pKa碱性药物的离子捕获，导致肝内滞留减少，但对肝内药物提取没有影响。
