The oral route for the administration of cytotoxic drugs: strategies to increase the efficiency and consistency of drug delivery.
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.
Bardelmeijer
H A
HA
Department of Clinical Chemistry, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam.
van Tellingen
O
O
Schellens
J H
JH
Beijnen
J H
JH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D006801:Humans; D007408:Intestinal Absorption; D006899:Mixed Function Oxygenases / Q000502:physiology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A