Johnson J A
Department of Pharmacy Practice, College of Pharmacy, University of Florida, Gainesville 32610, USA.
Int J Clin Pharmacol Ther. 2000 Feb;38(2):53-60. doi: 10.5414/cpp38053.
The International Conference on Harmonization has put forth a tripartite guideline addressing mechanisms by which regulatory agencies might be able to accept foreign clinical data. A major issue is the effect of ethnicity on the drug's pharmacokinetics, pharmacodynamics and/or safety. The purpose of this review was to determine whether the effects of ethnicity on pharmacokinetics are predictable. We also evaluated whether the premise that only pharmacokinetic processes which are biologically or biochemically mediated are likely to exhibit ethnic differences was supported by the literature. Bioavailability is determined by absorption, gut metabolism/transport and hepatic first pass metabolism. Absorption is usually a passive process and, as would be expected, no examples of ethnic differences in passive absorption were found in the literature. Direct evaluation of ethnic differences in gut metabolism/transport or hepatic first pass metabolism is largely lacking, although some studies suggest such differences exist. These differences would also be expected based on known ethnic differences in hepatic clearance of drugs. Ethnic differences in plasma protein-binding to the two major drug-binding proteins, alpha1-acid glycoprotein (AGP) and albumin, have been studied in several populations. Based on these studies, ethnic differences in plasma protein-binding for drugs which bind exclusively to albumin (e.g. acids) are uncommon. Conversely, ethnic differences in plasma protein-binding of drugs to AGP appear to be very common, with the studies consistently showing Caucasians have higher binding (lower plasma free fractions) than other ethnic groups. This difference appears, in all cases, to be explained by racial differences in plasma AGP concentration. Hepatic metabolism is the most common pharmacokinetic parameter for which there are ethnic differences. Differences have been documented in both oxidative and conjugative metabolism. Ethnic differences in hepatic metabolism are unpredictable by race (e.g. one racial group is not consistently higher or lower than another group) and specific enzyme (e.g. studies with different CYP3A4 substrates have yielded different results). Ethnic differences in renal tubular secretion have been documented, but also appear to be unpredictable, while differences in the passive processes of renal elimination, filtration and reabsorption, have not been observed. The literature supports the premise that pharmacokinetic processes which are active (e.g. involve a protein) are the ones with the potential for differences between ethnic groups while passive pharmacokinetic processes do not exhibit such differences. Based on the available literature, the drugs most likely to exhibit ethnic differences in their pharmacokinetics are those that undergo significant gut metabolism/transport and/or hepatic first pass metabolism; are highly bound to plasma proteins (especially AGP); or have hepatic metabolism as a major route of elimination.
国际协调会议已经提出了一项三方指南，阐述了监管机构能够接受国外临床数据的机制。一个主要问题是种族对药物的药代动力学、药效学和/或安全性的影响。本综述的目的是确定种族对药代动力学的影响是否可预测。我们还评估了文献是否支持仅生物或生化介导的药代动力学过程可能存在种族差异这一前提。生物利用度由吸收、肠道代谢/转运和肝脏首过代谢决定。吸收通常是一个被动过程，正如预期的那样，文献中未发现被动吸收存在种族差异的例子。虽然一些研究表明存在差异，但很大程度上缺乏对肠道代谢/转运或肝脏首过代谢中种族差异的直接评估。基于已知的药物肝脏清除率的种族差异，也可以预期存在这些差异。已经在多个人群中研究了血浆蛋白与两种主要药物结合蛋白，即α1-酸性糖蛋白（AGP）和白蛋白结合的种族差异。基于这些研究，仅与白蛋白结合的药物（如酸性药物）的血浆蛋白结合的种族差异并不常见。相反，药物与AGP的血浆蛋白结合的种族差异似乎非常普遍，研究一致表明高加索人的结合率更高（血浆游离分数更低）。在所有情况下，这种差异似乎都可以用血浆AGP浓度的种族差异来解释。肝脏代谢是存在种族差异的最常见药代动力学参数。氧化代谢和结合代谢中均有差异记录。肝脏代谢的种族差异无法通过种族预测（例如，一个种族群体并不总是高于或低于另一个群体），也无法通过特定酶预测（例如，对不同CYP3A4底物的研究得出了不同的结果）。肾小管分泌的种族差异已有记录，但似乎也无法预测，而肾脏排泄、滤过和重吸收的被动过程中的差异尚未观察到。文献支持这样的前提，即主动的药代动力学过程（例如涉及一种蛋白质）是不同种族群体之间可能存在差异的过程，而被动药代动力学过程则不存在这种差异。根据现有文献，药代动力学最有可能存在种族差异的药物是那些经历显著肠道代谢/转运和/或肝脏首过代谢的药物；与血浆蛋白高度结合（尤其是AGP）的药物；或以肝脏代谢作为主要消除途径的药物。
