, Volume 22, Issue 11, pp 1898-1905
Date: 21 Oct 2005

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.