Bardelmeijer H A, van Tellingen O, Schellens J H, Beijnen J H
Department of Clinical Chemistry, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam.
Invest New Drugs. 2000 Aug;18(3):231-41. doi: 10.1023/a:1006469621561.
There is an increasing interest to administer cytotoxic drugs to patients by the oral route. Quality of life issues, treatment advantages and pharmaco-economics are major arguments in favor of oral therapy. However, low or moderate bioavailability in combination with considerable interpatient variability are frequently observed which may reduce the feasibility of the oral route for this class of drugs with a generally narrow therapeutic window. Until recently, investigators focused on absorption enhancers which slightly damage the intestinal surface such as salicylates, methylxanthines and surfactants to improve the oral bioavailability of drugs. To date, a shift can be seen towards more subtle mechanisms to enhance the absorption. This review article focuses on two important mechanisms that determine the oral bioavailability of cytotoxic drugs. These include the presence of drug transporters in the intestinal epithelium pumping drugs into the intestinal lumen, such as MDR1 type P-glycoproteins, and first-pass elimination by cytochrome P450 isoenzymes (e.g. 3A4 and 3A5) or other enzymes in the intestines and/or liver. Currently preclinical and clinical studies are being performed to explore the feasibility of blocking these transporters/enzymes in order to achieve higher and less variable systemic drug levels after oral dosing. This review gives an update of the results of these studies. It is concluded however, that further research to unravel the processes involved in oral drug uptake is warranted to make the oral route a more efficient and consistent way of drug administration.
通过口服途径给患者使用细胞毒性药物的兴趣日益增加。生活质量问题、治疗优势和药物经济学是支持口服治疗的主要论据。然而，经常观察到生物利用度低或中等，同时患者间差异很大，这可能会降低口服途径对这类治疗窗通常较窄的药物的可行性。直到最近，研究人员一直专注于吸收增强剂，如水杨酸盐、甲基黄嘌呤和表面活性剂等对肠表面有轻微损害的物质，以提高药物的口服生物利用度。迄今为止，可以看到向更微妙的吸收增强机制转变。这篇综述文章重点关注决定细胞毒性药物口服生物利用度的两个重要机制。这些机制包括肠上皮细胞中存在将药物泵入肠腔的药物转运体，如MDR1型P-糖蛋白，以及细胞色素P450同工酶（如3A4和3A5）或肠道和/或肝脏中的其他酶进行的首过消除。目前正在进行临床前和临床研究，以探索阻断这些转运体/酶的可行性，以便在口服给药后获得更高且变异性更小的全身药物水平。这篇综述给出了这些研究结果的最新情况。然而，得出的结论是，有必要进一步研究以阐明口服药物摄取所涉及的过程，以使口服途径成为一种更有效且一致的给药方式。
