Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine

We have studied this possibility in more detail with the cytotoxic agent paclitaxel. Paclitaxel has become a very important drug in the treatment of cancer, and it is a very good substrate of P-glycoprotein, as was shown by in vitro transport studies in polarized monolayers of an MDR1transfected pig kidney epithelial cell line

A. Sparreboom; J. van Asperen; U. Mayer; A. H. Schinkel; J. W. Smit; D. K. F. Meijer; P. Borst; W. J. Nooijen; J. H. Beijnen; O. van Tellingen

2002

Scholarcy highlights

  • P-glycoproteins, encoded by the human MDR1 or the murine mdr1a and mdr1b genes are drug efflux pumps localized in the plasma membrane
  • Further studies with vinblastine in these mice demonstrated a lower body clearance and a reduced fecal excretion, which suggested that P-glycoprotein may contribute to drug elimination by mediating biliary excretion andor limitinguptake from the intestinal lumen after hepatobiliary excretion. We have studied this possibility in more detail with the cytotoxic agent paclitaxel. Paclitaxel has become a very important drug in the treatment of cancer, and it is a very good substrate of P-glycoprotein, as was shown by in vitro transport studies in polarized monolayers of an MDR1transfected pig kidney epithelial cell line
  • If P-glycoprotein in the intestinal mucosa of mice would limit the bioavailability of paclitaxel, this should result in higher plasma levels in mdr1a(ϪϪ) mice than in wt mice after oral drug administration
  • Our results show that the disruption of the mdr1a Pglycoprotein gene in mice results in a drastic alteration in the pharmacokinetics of paclitaxel, a cytotoxic drug increasingly used in the treatment of cancer patients
  • P-glycoprotein at the lumenal side of the intestinal epithelium appears to be an important component of the defense against substrate drugs such as paclitaxel
  • The disruption of this defense leads to a substantial increase in bioavailability after oral administration in the mdr1a(ϪϪ) mice
  • A remarkable finding is the substantial fraction of the dose recovered in the intestinal contents of wt animals with cannulated gall bladder receiving paclitaxel by i.v. administration

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