Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview

Abstract

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. The Oncologist 2002;7:516-530

Dietary Flavonoids Modulate CYP2C to Improve Drug Oral Bioavailability and Their Qualitative/Quantitative Structure–Activity Relationship

“…However, in addition to enzyme regulation efficacy, an acceptable safety profile is of prime importance for a candidate CYP2C modulator. To avoid unwanted drug responses, CYP2C inhibition should be temporary and reversible (17). Ideally, the inhibition effects would be best confined to the gastrointestinal tract and liver, where CYP2C is abundantly and broadly distributed (18), rather than entering the body to produce systemic effects.…”

Enhanced oral paclitaxel bioavailability after administration of paclitaxel-loaded nanosponges

“…Unfortunately, paclitaxel has a very low level of oral bioavailability, at less than 10% (van Asperen et al, 1998;Bardelmeijer et al, 2000;Malingre et al, 2001;Gao et al, 2003). This poor bioavailability level results from limited aqueous solubility and dissolution, affinity for the intestinal and liver cytochrome P450 (like CYP3A4) metabolic enzymes, and the multidrug efflux pump P-glycoprotein (P-gp), which is present abundantly in the gastrointestinal tract Malingre et al, 2001;Zuylen et al, 2001;Kruijtzer et al, 2002). In a proof-of concept study, the oral bioavailability of paclitaxel increased from only 11% in wild-type mice to 35% in mice that were homozygous for a disruption of the mdr1a gene, demonstrating that P-gp plays a major role in reducing the bioavailability of this drug (Sparreboom et al, 1997).…”

Interactions of Cyclosporin A with Breast Cancer Resistance Protein

“…BCRP has been demonstrated to be present on the apical membrane of intestinal epithelium and to limit the oral absorption of topotecan in mouse and human (Jonker et al, 2000;Kruijtzer et al, 2002a). Given the liver and intestinal localization pattern, BCRP, similar to P-gp, may act as a barrier to uptake and limit the oral bioavailability of drugs as well as mediating hepatobiliary excretion of drugs (Jonker et al, 2000;Jorritsma et al, 2002;Kruijtzer et al, 2002b).…”