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P-glycoprotein and bioavailability-implication of polymorphism.

Y Liu1, M Hu

  • 1Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman 99164-6510, USA.

Clinical Chemistry and Laboratory Medicine
|November 30, 2000
PubMed
Summary
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P-glycoprotein (P-gp) effluxes drugs, impacting bioavailability and multidrug resistance (MDR). Research in knockout mice and cancer cells highlights P-gp

Area of Science:

  • Pharmacology and Drug Transport
  • Molecular Biology and Biochemistry
  • Cancer Chemotherapy and Drug Resistance

Background:

  • P-glycoprotein (P-gp) acts as an efflux pump, reducing drug bioavailability by expelling molecules from cells.
  • Initially linked to multidrug resistance (MDR) in cancer, P-gp's role in systemic drug bioavailability is a more recent discovery.
  • Other transporters, like multidrug resistance-related proteins (MRPs), also contribute to MDR.

Purpose of the Study:

  • To explore the impact of P-glycoprotein on drug bioavailability at both systemic and cellular levels.
  • To investigate the role of P-gp in restricting drug entry into the central nervous system (CNS) via the blood-brain barrier (BBB).
  • To examine the implications of P-gp polymorphism on drug bioavailability and potential drug interactions.

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Main Methods:

  • Utilized MDR1 knockout mice to assess systemic drug bioavailability.
  • Investigated P-gp expression levels at the blood-brain barrier (BBB).
  • Studied the functional implications of P-gp polymorphism in rodent models and human cancer cells.

Main Results:

  • MDR1 knockout mice showed significantly improved systemic bioavailability of several drugs.
  • High P-gp expression was confirmed at the BBB, essential for limiting drug entry into the CNS.
  • P-gp polymorphism has been observed in human cancer cells, with functional implications studied in rodents, supporting its role in restricting anticancer drug bioavailability and CNS toxicity.

Conclusions:

  • P-glycoprotein plays a crucial role in limiting the tissue bioavailability of anticancer drugs and CNS drug entry.
  • While P-gp's impact on human systemic bioavailability is less defined than in knockout mice, its existence suggests potential effects on drug absorption and interactions.
  • The development of P-gp inhibitors and the discovery of natural inhibitors are expected to significantly influence the bioavailability of anticancer and CNS drugs.