Structural features determining the intestinal epithelial permeability and efflux of novel HIV-1 protease inhibitors

Lucia Lazorova, Ina Hubatsch, Jenny K. Ekegren, Johan Gising, Daisuke Nakai, Noha M. Zaki, Christel A S Bergström, Ulf Norinder, Mats Larhed, Per Artursson

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Abstract

The primary aim of this study was to identify structural features that alter the intestinal epithelial permeability and efflux in a series of novel HIV-1 protease inhibitors (PIs). Eleven PIs were selected containing a tertiary alcohol in a transition-state mimicking scaffold, in which two substituents (R1 and R2) were varied systematically. Indinavir was selected as a reference compound. The apical-to-basolateral permeability was investigated in 2/4/A1 and Caco-2 monolayers. In addition, the basolateral-to-apical permeability was investigated in the Caco-2 monolayers and the efflux ratios were calculated. The absence of active drug transport processes in 2/4/A1 cells allowed identification and modeling of structural elements affecting the passive permeability. For instance, small aromatic R1 substituents and a small (bromo-) R2 substituent were associated with a high passive permeability. Efflux studies in Caco-2 cells indicated that amide-substituted neutral hydrophobic amino acids, such as valine and leucine, in the R1 position, reduced the apical-to-basolateral transport and enhanced the efflux. We conclude that our investigation revealed structural features that alter the intestinal epithelial permeability and efflux in the series of PIs and hope that these results can contribute to the synthesis of PIs with improved permeability and limited efflux properties.

Original languageEnglish
Pages (from-to)3763-3772
Number of pages10
JournalJournal of Pharmaceutical Sciences
Volume100
Issue number9
DOIs
Publication statusPublished - Sep 2011
Externally publishedYes

Keywords

  • Absorption
  • ADME
  • Caco-2 cells
  • Drug design
  • Drug transport
  • HIV/AIDS
  • Intestinal absorption
  • P-glycoprotein
  • Passive diffusion/transport
  • Permeability

Cite this

Lazorova, L., Hubatsch, I., Ekegren, J. K., Gising, J., Nakai, D., Zaki, N. M., Bergström, C. A. S., Norinder, U., Larhed, M., & Artursson, P. (2011). Structural features determining the intestinal epithelial permeability and efflux of novel HIV-1 protease inhibitors. Journal of Pharmaceutical Sciences, 100(9), 3763-3772. https://doi.org/10.1002/jps.22570