Improvement of oral drug treatment by temporary inhibition of drug transporters and/or cytochrome P450 in the gastrointestinal tract and liver: an overview.
The oral bioavailability of many cytotoxic drugs is low and/or highly variable. This can be caused by high affinity for drug transporters and activity of metabolic enzymes in the gastrointestinal tract and liver. In this review, we will describe the main involved drug transporters and metabolic enzymes and discuss novel methods to improve oral treatment of affected substrate drugs. Results of preclinical and clinical phase I and II studies will be discussed in which affected substrate drugs, such as paclitaxel, docetaxel, and topotecan, are given orally in combination with an inhibitor of drug transport or drug metabolism. Future randomized studies will, hopefully, confirm that this strategy for oral treatment is at least as equally effective and safe as standard intravenous administration of these drugs.
Kruijtzer
C M F
CM
Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Beijnen
J H
JH
Schellens
J H M
JH
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics; D001682:Biological Availability; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D009363:Neoplasm Proteins; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics
C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D003577:Cytochrome P-450 Enzyme System