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

In spite of the host of functions speculatively attributed to the mdr1-type P-gps, we found no physiological abnormalities in either strain

A. H. Schinkel; U. Mayer; E. Wagenaar; C. A. A. M. Mol; L. van Deemter; J. J. M. Smit; M. A. van der Valk; A. C. Voordouw; H. Spits; O. van Tellingen; J. M. J. M. Zijlmans; W. E. Fibbe; P. Borst


Scholarcy highlights

  • The discovery of compounds that inhibit P-gp activity has led to attempts to inhibit P-gp activity in tumors of patients to improve their response to chemotherapy
  • The mdr1b gene was inactivated by homologous recombination in embryonic stem cells as outlined in Fig. 1 A
  • Despite the very high mdr1b expression normally found in the adrenal gland and in the pregnant uterus of wild-type mice, mdr1b mice displayed normal viability, fertility, and lifespan, and no obvious spontaneous physiological abnormalities were observed
  • An immunoassay demonstrated that more than 95% of the radioactivity excreted in bile of wild-type and mdr1a1b mice represented digoxin and closely related, pharmacologically active metabolites
  • This result shows that the liver harbors a substantialdigoxin excretion capacity that is distinct from the mdr1-type P-gps
  • The limited effect of the mdr1b P-gp by itself on the plasma pharmacokinetics of digoxin appears to result from the presence of effective alternative digoxin excretion mechanisms in both liver and kidney, and from the fact that mdr1b is not expressed in the intestinal epithelium
  • Our analysis of possible functional abnormalities has not been exhaustive it shows that the mdr1-type P-gps are not vital to basic liver, kidney, or intestinal function, nor to the functions of the brain, adrenal gland, ovaries, or uterus during pregnancy

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