Caco-2 permeability, P-glycoprotein transport ratios and brain penetration of heterocyclic drugs

Int J Pharm. 2003 Sep 16;263(1-2):113-22. doi: 10.1016/s0378-5173(03)00372-7.


In this study the gastrointestinal absorption and P-glycoprotein (Pgp) efflux transport of heterocyclic drugs was investigated with the Caco-2 cell model. Based on the calculation of the physico-chemical properties a good oral absorption was predicted for all the drugs tested in this study which corresponded well with the measured Caco-2 permeabilities (Papp). Generally a high permeability of the tested heterocyclic drugs was measured being in agreement with earlier published human in vivo absorption data. Based on the transport data of domperidone and verapamil it was found that the Pgp efflux transporter was expressed in the Caco-2 cells. Many of the drugs tested were indicated to be potential Pgp efflux substrates. Since Pgp is expressed at the Blood Brain Barrier (BBB) as well, it was expected that CNS penetration will be impaired if a drug is a Pgp substrate. However, no correlation could be found between brain penetration in rats and the Pgp efflux ratio as measured with the Caco-2 cells. From the data it is concluded that Pgp efflux ratio's as determined in in vitro High Throughput Screening (HTS) tests, where the transport conditions are fixed (pH gradient, concentration, etc.), cannot routinely be used to predict a possible limited brain penetration.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Brain / drug effects
  • Brain / metabolism*
  • Caco-2 Cells
  • Cell Membrane Permeability* / drug effects
  • Heterocyclic Compounds / pharmacokinetics*
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Protein Transport / drug effects
  • Protein Transport / physiology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Heterocyclic Compounds