Pharmaceutical Research

, Volume 15, Issue 5, pp 719–725 | Cite as

Transport Characteristics of Peptidomimetics. Effect of the Pyrrolinone Bioisostere on Transport Across Caco-2 Cell Monolayers

  • Masao Sudoh
  • Giovanni M. Pauletti
  • Wenqing Yao
  • William Moser
  • Akihisa Yokoyama
  • Alexander Pasternak
  • Paul A. Sprengeler
  • Amos B. SmithIII
  • Ralph Hirschmann
  • Ronald T. Borchardt


Purpose. To compare the permeation characteristics of amide bond-containing HIV-1 protease inhibitors and their pyrrolinone-containing counterparts across Caco-2 cell monolayers, a model of the intestinal mucosa.

Methods. Transepithelial transport and cellular uptake of three pairs of amide bond-containing and pyrrolinone-based peptidomimetics were assessed in the presence and absence of cyclosporin A using the Caco-2 cell culture model. The potential of the peptidomimetics to interact with biological membranes was estimated by IAM chromatography.

Results. In the absence of cyclosporin A, apical (AP) to basolateral (BL) flux of all compounds studied was less than the flux determined in the opposite direction (i.e., BL-to-AP). The ratio of the apparent permeability coefficients (Papp) calculated for the BL-to-AP and AP-to-BL transport (PBL⇒AP/PAP⇒BL) varied between 1.7 and 36.2. When individual pairs were compared, PBL⇒AP/PAP⇒BL ratios of the pyrrolinone-containing compounds were 1.5 to 11.5 times greater than those determined for the amide bond-containing analogs. Addition of 25 μM cyclosporin A to the transport buffer reduced the PBL⇒AP /PAP⇒BL ratios for all protease inhibitors to a value close to unity. Under these conditions, the amide bond-containing peptidomimetics were at least 1.6 to 2.8 times more able to permeate Caco-2 cell monolayers than were the pyrrolinone-containing compounds. The intrinsic uptake characteristics into Caco-2 cells determined in the presence of 25 μM cyclosporin A were slightly greater for the amide bond-containing protease inhibitors than for the pyrrolinone-containing analogs. These uptake results are consistent with the transepithelial transport results determined across this in vitro model of the intestinal mucosa.

Conclusions. The amide bond-containing and pyrrolinone-based peptidomimetics are substrates for apically polarized efflux systems present in Caco-2 cell monolayers. The intrinsic permeabilities of the amide bond-containing protease inhibitors are slightly greater than the intrinsic permeabilities of the pyrrolinone-based analogs through Caco-2 cell monolayers.

peptidomimetics pyrrolinone bioisostere Caco-2 cells membrane permeability polarized efflux systems 


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Copyright information

© Plenum Publishing Corporation 1998

Authors and Affiliations

  • Masao Sudoh
    • 1
  • Giovanni M. Pauletti
    • 1
    • 2
  • Wenqing Yao
    • 3
  • William Moser
    • 3
  • Akihisa Yokoyama
    • 3
  • Alexander Pasternak
    • 3
  • Paul A. Sprengeler
    • 3
  • Amos B. SmithIII
    • 3
  • Ralph Hirschmann
    • 3
  • Ronald T. Borchardt
    • 1
  1. 1.Department of Pharmaceutical ChemistryThe University of KansasLawrence
  2. 2.School of PharmacyTexas Tech University Health Sciences CenterAmarillo
  3. 3.Department of ChemistryUniversity of PennsylvaniaPhiladelphia

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