Chiou W L, Chung S M, Wu T C, Ma C
Department of Pharmaceutics and Pharmacodynamics, College of Pharmacy, The University of Illinois at Chicago, 60612, USA.
Int J Clin Pharmacol Ther. 2001 Mar;39(3):93-101. doi: 10.5414/cpp39093.
The potential absorption-limiting effect of intestinal efflux transporters such as P-glycoprotein (P-gp) has been well recognized, primarily based on results of numerous Caco-2 cell studies showing that flux, permeability, or transport clearance of drugs from the basolateral to the apical (B --> A) compartment is greater than that from the apical to the basolateral (A --> B) compartment. Except for very limited examples such as celiprolol, talinolol, pafenolol and paclitaxel, the potential clinical impact of these transporters on oral absorption of the vast number of commonly prescribed drug substrates in humans has not been closely examined to date.
To evaluate whether these efflux transporters may play a significant role in limiting oral absorption of 13 commonly used drugs (digoxin, etoposide, felodipine, fexofenadine, furosemide, indinavir, losartan, nadolol, propranolol, ritonavir, saquinavir, tacrolimus, and verapamil) in humans.
Drug absorption properties such as the rate (as judged by the Cmax and tmax) and extent (as judged by AUC or urinary excretion of drugs) of absorption as a function of dose, as well as the completeness of oral absorption were obtained from the literature.
The absorption properties of these 13 drugs are not consistent with absorption-retarding expectations from in vitro studies because they all show apparent dose-independent kinetics in absorption or bioavailability and completeness of oral absorption is shown for most of the drugs evaluated.
In spite of being substrates of intestinal efflux transporters such as P-gp, the in vivo oral absorption of 13 drugs examined apparently is not significantly impeded by efflux transporters. Thus, there may exist an apparent discrepancy between in vitro "expectations" and in vivo results; potential reasons for this are discussed. The present findings, however, do not de-emphasize potential in vivo importance of efflux transporters in affecting (increasing or decreasing) oral absorption of certain substrate drugs, especially those with low to moderate intestinal permeability and with low therapeutic index, or the importance of efflux transporters in the study of mechanisms of drug absorption and some potentially clinically significant drug-drug and drug-food interactions.
肠道外排转运体（如P-糖蛋白，P-gp）的潜在吸收限制作用已得到充分认识，这主要基于众多Caco-2细胞研究结果，这些研究表明药物从基底外侧到顶端（B→A）隔室的通量、渗透率或转运清除率大于从顶端到基底外侧（A→B）隔室。除了塞利洛尔、他林洛尔、帕非洛尔和紫杉醇等非常有限的例子外，这些转运体对人类大量常用药物底物口服吸收的潜在临床影响迄今尚未得到密切研究。
评估这些外排转运体是否可能在限制13种常用药物（地高辛、依托泊苷、非洛地平、非索非那定、呋塞米、茚地那韦、氯沙坦、纳多洛尔、普萘洛尔、利托那韦、沙奎那韦、他克莫司和维拉帕米）在人体内的口服吸收中起重要作用。
从文献中获取药物吸收特性，如吸收速率（通过Cmax和tmax判断）和程度（通过AUC或药物尿排泄判断）作为剂量的函数，以及口服吸收的完整性。
这13种药物的吸收特性与体外研究预期的吸收延迟不一致，因为它们在吸收或生物利用度方面均表现出明显的剂量非依赖性动力学，并且大多数评估药物的口服吸收完整性良好。
尽管这13种药物是肠道外排转运体（如P-gp）的底物，但它们在体内的口服吸收显然未受到外排转运体的显著阻碍。因此，体外“预期”与体内结果之间可能存在明显差异；本文讨论了潜在原因。然而，本研究结果并未忽视外排转运体在影响（增加或减少）某些底物药物口服吸收方面的潜在体内重要性，特别是那些肠道通透性低至中等且治疗指数低的药物，也未忽视外排转运体在药物吸收机制研究以及一些潜在临床显著的药物-药物和药物-食物相互作用研究中的重要性。
