The oral route for the administration of cytotoxic drugs: strategies to increase the efficiency and consistency of drug delivery

被引:33
作者
Bardelmeijer, HA
van Tellingen, O
Schellens, JHM
Beijnen, JH
机构
[1] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Clin Chem, NL-1066 CX Amsterdam, Netherlands
[2] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Med Oncol, NL-1066 CX Amsterdam, Netherlands
[3] Slotervaart Hosp, Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands
[4] Univ Utrecht, Fac Pharm, Div Drug Toxicol, Utrecht, Netherlands
关键词
cytotoxic drugs; oral administration; bioavailability; variability; P-glycoprotein; CYP3A;
D O I
10.1023/A:1006469621561
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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, methylxantines 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.
引用
收藏
页码:231 / 241
页数:11
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