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Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins.

The mdr1-type P-glycoproteins (P-gps) confer multidrug resistance to cancer cells by active extrusion of a wide range of drugs from the cell. To study their physiological roles, we have generated mice genetically deficient in the mdr1b gene [mdr1b (-/-) mice] and in both the mdr1a and mdr1b genes [mdr1a/1b (-/-) mice]. In spite of the host of functions speculatively attributed to the mdrl-type P-gps, we found no physiological abnormalities in either strain. Viability, fertility, and a range of histological, hematological, serum-chemical, and immunological parameters were not abnormal in mdr1a/1b (-/-) mice. The high level of mdrlb P-gp normally present in the pregnant uterus did not protect fetuses from a drug (digoxin) in the bloodstream of the mother, although the protein did reduce drug accumulation in the adrenal gland and ovaries. Pharmacologically, mdr1a/1b (-/-) mice behaved similarly to the previously analyzed mdr1a (-/-) mice, displaying, for instance, increased brain penetration and reduced elimination of digoxin. However, both mdr1a and mdr1b P-gps contributed to the extrusion of rhodamine from hematopoietic progenitor cells, suggesting a potential role for the endogenous mdr1-type P-gps in protection of bone marrow against cytotoxic anticancer drugs. This, and the normal viability of mdr1a/1b (-/-) mice, has implications for the use of P-gp-blocking agents in cancer and other chemotherapy. mdr1a/1b (-/-) mice should provide a useful model system to further test the pharmacological roles of the drug-transporting P-gps and to analyze the specificity and effectivity of P-gp-blocking drugs.

Pubmed ID: 9108099

Authors

  • Schinkel AH
  • Mayer U
  • Wagenaar E
  • Mol CA
  • van Deemter L
  • Smit JJ
  • van der Valk MA
  • Voordouw AC
  • Spits H
  • van Tellingen O
  • Zijlmans JM
  • Fibbe WE
  • Borst P

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

April 15, 1997

Associated Grants

None

Mesh Terms

  • Animals
  • Digoxin
  • Drug Resistance, Multiple
  • Embryonic and Fetal Development
  • Enzyme Inhibitors
  • Female
  • Mice
  • Mice, Knockout
  • P-Glycoprotein
  • Pregnancy