Pharmaceutical Research

, Volume 22, Issue 11, pp 1898–1905

Tissue Distribution of Indinavir Administered as Solid Lipid Nanocapsule Formulation in mdr1a (+/+) and mdr1a (−/−) CF-1 Mice

  • Manuela Pereira de Oliveira
  • Emmanuel Garcion
  • Nicolas Venisse
  • Jean-Pierre Benoît
  • William Couet
  • Jean-Christophe Olivier
Research Paper

DOI: 10.1007/s11095-005-7147-6

Cite this article as:
Pereira de Oliveira, M., Garcion, E., Venisse, N. et al. Pharm Res (2005) 22: 1898. doi:10.1007/s11095-005-7147-6

Purpose

Due to protease inhibitor (PI) efflux transport by P-glycoprotein (P-gp), insufficient PI concentrations result in low ongoing HIV replication in the so-called virus sanctuaries (brain and testes). The aim of the present study was to evaluate indinavir-loaded nanocapsules (Ind-LNC) including Solutol® HS15, an excipient reported to possess in vitro P-gp inhibiting properties, as a means to improve indinavir distribution into brain and testes of mice.

Methods

Normal mdr1a (+/+) or P-gp-deficient mdr1a (−/−) CF-1 mice were dosed with Ind-LNC (10 mg indinavir/kg, i.v.). At 30 min postadministration, indinavir was determined in plasma, brain, testes, as well as in kidneys, liver, and heart by LC-MS/MS, and tissue/plasma concentration ratios were calculated. Results were compared with those of control groups that received an indinavir solution (Ind-Sol).

Results

Using Ind-Sol, ratios were 21.3- and 3.3-fold higher in brains and testes of mdr1a (−/−) mice than of mdr1a (+/+) mice, respectively, whereas in the other organs ratios were not significantly different between the two substrains. When Ind-LNC was used, a similar [mdr1a (−/−) vs. mdr1a (+/+) mice] trend was observed. Moreover, ratios were found to be significantly increased (1.9-fold increase in average) in most organs (brain and testes in particular) with Ind-LNC compared to Ind-Sol, regardless of the substrain used.

Conclusions

In agreement with previous works, P-gp governs at least in part indinavir uptake into brain and testes. LNC formulation increased indinavir uptake in brain and testes by mechanisms other than, or additional to, P-gp inhibition.

Key Words

CF-1 miceindinavirP-glycoproteinsolid lipid nanocapsuleSolutol® HS15

Abbreviations

Ind-LNC

indinavir-loaded lipid nanocapsules

Ind-Sol

indinavir solution

LNC

lipid nanocapsule

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Manuela Pereira de Oliveira
    • 1
  • Emmanuel Garcion
    • 2
  • Nicolas Venisse
    • 1
    • 3
  • Jean-Pierre Benoît
    • 2
  • William Couet
    • 1
    • 3
  • Jean-Christophe Olivier
    • 1
  1. 1.Faculté de Médecine & PharmacieEA3809 “Pharmacologie des Médicaments Anti-Infectieux”, Pôle Biologie-SantéPoitiers CEDEXFrance
  2. 2.Inserm-U 646 Bâtiment IBTAngersFrance
  3. 3.Faculté de Médecine & Pharmacie, Laboratoire de PharmacocinétiqueCentre Hospitalo-Universitaire de Poitiers, Pôle Biologie-SantéPoitiers CEDEXFrance