Tacrolimus is a class II low-solubility high-permeability drug: the effect of P-glycoprotein efflux on regional permeability of tacrolimus in rats

J Pharm Sci. 2002 Mar;91(3):719-29. doi: 10.1002/jps.10041.


The objective of this study is to investigate the role of P-glycoprotein (P-gp), a membrane efflux pump associated with multidrug resistance (MDR) and a known substrate for tacrolimus, in determining the regional intestinal permeability of tacrolimus in rats. Thus, isolated segments of rat jejunum, ileum, or colon were perfused with tacrolimus solutions containing polyethoxylated hydrogenated castor oil 60 surfactant, and with or without verapamil, a P-gp substrate used to reverse the MDR phenotype. The results indicated that the intrinsic permeability of tacrolimus in the jejunum, calculated on the basis of the concentration of non-micellized free tacrolimus, was quite high ( approximately 1.4 x 10(-4) cm/s). The apparent permeability (P(app)) in the jejunum was unaffected by the presence of verapamil; however, the P(app) in the ileum and the colon increased significantly in the presence of verapamil and were similar to the values observed in the jejunum. The results suggest that systemic absorption of tacrolimus from the gastrointestinal tract could be significantly affected by P-gp efflux mechanisms. It is also possible that differences in P-gp function at various intestinal sites in a subject or at a given intestinal site in various subjects could lead to large intra- and interindividual variability in bioavailability of tacrolimus following oral administration.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
  • Animals
  • Biological Availability
  • Caco-2 Cells
  • Chromatography, High Pressure Liquid
  • Humans
  • Immunosuppressive Agents / chemistry*
  • Immunosuppressive Agents / pharmacokinetics
  • Intestinal Absorption
  • Jejunum / drug effects
  • Jejunum / metabolism
  • Male
  • Models, Biological
  • Perfusion
  • Rats
  • Solubility
  • Surface-Active Agents / chemistry
  • Surface-Active Agents / pharmacology
  • Tacrolimus / chemistry*
  • Tacrolimus / pharmacokinetics
  • Water / metabolism


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Immunosuppressive Agents
  • Surface-Active Agents
  • Water
  • Tacrolimus