Garrison Kimberly L, Sahin Selma, Benet Leslie Z
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California.
Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.
J Pharm Sci. 2015 Sep;104(9):3229-35. doi: 10.1002/jps.24505. Epub 2015 May 25.
This study was conducted to determine the number of drugs exhibiting flip-flop pharmacokinetics following oral (p.o.) dosing from immediate-release dosage forms and if they exhibit a common characteristic that may be predicted based on BDDCS classification. The literature was searched for drugs displaying flip-flop kinetics (i.e., absorption half-life larger than elimination half-life) in mammals in PubMed, via internet search engines and reviewing drug pharmacokinetic data. Twenty two drugs were identified as displaying flip-flop kinetics in humans (13 drugs), rat (nine drugs), monkey (three drugs), horse (two drugs), and/or rabbit (two drugs). Nineteen of the 22 drugs exhibiting flip-flop kinetics were BDDCS Classes 3 and 4. One of the three exceptions, meclofenamic acid (Class 2), was identified in the horse; however, it would not exhibit flip-flop kinetics in humans where the p.o. dosing terminal half-life is 1.4 h. The second, carvedilol, can be explained based on solubility issues, but the third sapropterin dihydrochloride (nominally Class 1) requires further consideration. The few drugs displaying p.o. flip-flop kinetics in humans are predominantly BDDCS Classes 3 and 4. New molecular entities predicted to be BDDCS Classes 3 and 4 could be liable to exhibit flip-flop kinetics when the elimination half life is short and should be suspected to be substrates for intestinal transporters.
本研究旨在确定口服速释剂型给药后呈现出翻转药代动力学的药物数量，以及它们是否具有基于生物药剂学分类系统（BDDCS）分类可预测的共同特征。通过在PubMed中检索、利用互联网搜索引擎并查阅药物药代动力学数据，在文献中查找在哺乳动物中呈现翻转动力学（即吸收半衰期大于消除半衰期）的药物。已确定有22种药物在人类（13种药物）、大鼠（9种药物）、猴子（3种药物）、马（2种药物）和/或兔子（2种药物）中呈现翻转动力学。呈现翻转动力学的22种药物中有19种属于BDDCS 3类和4类。三个例外之一的甲氯芬那酸（2类）是在马中发现的；然而，在人类中口服给药时其末端半衰期为1.4小时，不会呈现翻转动力学。第二个药物卡维地洛可基于溶解度问题来解释，但第三个药物盐酸沙丙蝶呤（名义上为1类）需要进一步研究。在人类中呈现口服翻转动力学的少数药物主要属于BDDCS 3类和4类。预测为BDDCS 3类和4类的新分子实体在消除半衰期较短时可能易于呈现翻转动力学，并且应怀疑是肠道转运体的底物。
