DOI: 10.1073/pnas.94.8.4028. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins

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

10.1073/pnas.94.8.4028

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

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 themdr1bgene [mdr1b(−/−) mice] and in both themdr1aandmdr1bgenes [mdr1a/1b(−/−) mice]. In spite of the host of functions speculatively attributed to the mdr1-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 inmdr1a/1b(−/−) mice. The high level of mdr1b 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 analyzedmdr1a(−/−) 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 ofmdr1a/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.

Bibliography

Schinkel, A. H., Mayer, U., Wagenaar, E., Mol, C. A. A. M., van Deemter, L., Smit, J. J. M., van der Valk, M. A., Voordouw, A. C., Spits, H., van Tellingen, O., Zijlmans, J. M. J. M., Fibbe, W. E., & Borst, P. (1997). Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting)âP-glycoproteins. Proceedings of the National Academy of Sciences, 94(8), 4028â4033.

Authors 13

Alfred H. Schinkel (first)
Ulrich Mayer (additional)
Els Wagenaar (additional)
Carla A. A. M. Mol (additional)
Liesbeth van Deemter (additional)
Jaap J. M. Smit (additional)
Martin A. van der Valk (additional)
Arie C. Voordouw (additional)
Hergen Spits (additional)
Olaf van Tellingen (additional)
J. Mark J. M. Zijlmans (additional)
Willem E. Fibbe (additional)
Piet Borst (additional)

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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:43 a.m.)
Deposited	2 years, 4 months ago (April 22, 2023, 8:31 a.m.)
Indexed	2 days, 14 hours ago (Aug. 23, 2025, 9:14 p.m.)
Issued	28 years, 4 months ago (April 15, 1997)
Published	28 years, 4 months ago (April 15, 1997)
Published Online	28 years, 4 months ago (April 15, 1997)
Published Print	28 years, 4 months ago (April 15, 1997)

Funders 0

None

BibTeX

@article{Schinkel_1997, title={Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins}, volume={94}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.94.8.4028}, DOI={10.1073/pnas.94.8.4028}, number={8}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Schinkel, Alfred H. and Mayer, Ulrich and Wagenaar, Els and Mol, Carla A. A. M. and van Deemter, Liesbeth and Smit, Jaap J. M. and van der Valk, Martin A. and Voordouw, Arie C. and Spits, Hergen and van Tellingen, Olaf and Zijlmans, J. Mark J. M. and Fibbe, Willem E. and Borst, Piet}, year={1997}, month=apr, pages={4028–4033} }

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