Targeting intestinal transporters for optimizing oral drug absorption

Curr Drug Metab. 2010 Nov;11(9):730-42. doi: 10.2174/138920010794328850.


While the oral exposure continues to be the major focus, the chemical space of recent drug discovery is apparently trending towards more hydrophilic libraries, due to toxicity and drug-interactions issues usually reported with lipophilic drugs. This trend may bring in challenges in optimizing the membrane permeability and thus the oral absorption of new chemical entities. It is now apparent that the influx transporters such as peptide transporter 1 (PepT1), organic-anion transporting polypeptides (OATPs), monocarboxylate transporters (MCT1) facilitate, while efflux pumps (e.g. P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)) limit oral absorption of drugs. This review will focus on intestinal transporters that may be targeted to achieve optimal clinical oral plasma exposure for hydrophilic and polar drugs. The structure, mechanism, structure-activity relationships and the clinical examples on the functional role of these transporters in the drug absorption was discussed. Physicochemical properties, lipophilicity and hydrogen-bonding ability, show good correlation with transport activity for efflux pumps. Although several attempts were made to describe the structural requirements based on pharmacophore modeling, lack of crystal structure of transporters impeded identification of definite properties for transporter affinity and favorable transport activity. Furthermore, very few substrate drug datasets are currently available for the influx transporters to derive any clear relationships. Unfortunately, gaps also exist in the translation of in vitro end points to the clinical relevance of the transporter(s) involved. However, it may be qualitatively generalized that targeting intestinal transporters are relevant for drugs with high solubility and/or low passive permeability i.e. a class of compounds identified as Class III and Class IV according to the Biopharmaceutic Classification System (BCS) and the Biopharmaceutic Drug Disposition Classification System (BDDCS). A careful considerations to oral dose based on the transporter clearance (V(max)/K(m)) capacity is needed in targeting a particular transporter. For example, low affinity and high capacity uptake transporters such as PEPT1 and MCT1 may be targeted for high oral dose drugs.

Publication types

  • Review

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Humans
  • Intestinal Absorption
  • Intestinal Mucosa / enzymology
  • Intestinal Mucosa / metabolism*
  • Membrane Transport Proteins / metabolism*
  • Models, Biological*
  • Pharmaceutical Preparations / administration & dosage*
  • Pharmaceutical Preparations / classification
  • Pharmacokinetics*
  • Prodrugs / administration & dosage
  • Prodrugs / pharmacokinetics


  • Membrane Transport Proteins
  • Pharmaceutical Preparations
  • Prodrugs