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

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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.

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Abbreviations

Ind-LNC:

indinavir-loaded lipid nanocapsules

Ind-Sol:

indinavir solution

LNC:

lipid nanocapsule

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Acknowledgment

We are grateful for the excellent technical assistance of Mrs. Isabelle Lamarche.

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Authors and Affiliations

  1. Faculté de Médecine & Pharmacie, EA3809 “Pharmacologie des Médicaments Anti-Infectieux”, Pôle Biologie-Santé, 40 av. du Recteur Pineau, 86022, Poitiers CEDEX, France

    Manuela Pereira de Oliveira, Nicolas Venisse, William Couet & Jean-Christophe Olivier

  2. Inserm-U 646 Bâtiment IBT, 10 rue André Boquel, 49100, Angers, France

    Emmanuel Garcion & Jean-Pierre Benoît

  3. Faculté de Médecine & Pharmacie, Laboratoire de Pharmacocinétique, Centre Hospitalo-Universitaire de Poitiers, Pôle Biologie-Santé, 86022, Poitiers CEDEX, France

    Nicolas Venisse & William Couet

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  1. Manuela Pereira de Oliveira
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  2. Emmanuel Garcion
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  3. Nicolas Venisse
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  4. Jean-Pierre Benoît
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  6. Jean-Christophe Olivier
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Correspondence to Jean-Christophe Olivier.

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Pereira de Oliveira, M., Garcion, E., Venisse, N. et al. Tissue Distribution of Indinavir Administered as Solid Lipid Nanocapsule Formulation in mdr1a (+/+) and mdr1a (−/−) CF-1 Mice. Pharm Res 22, 1898–1905 (2005). https://doi.org/10.1007/s11095-005-7147-6

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