Tissue distribution of indinavir administered as solid lipid nanocapsule formulation in mdr1a (+/+) and mdr1a (-/-) CF-1 mice.
OBJECTIVE
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 post-administration, 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.
Pereira de Oliveira
Manuela
M
Faculté de Médecine & Pharmacie, EA3809 Pharmacologie des Médicaments Anti-Infectieux, Pôle Biologie-Santé, 40 av. du Recteur Pineau, 86022 Poitiers CEDEX, France.
Garcion
Emmanuel
E
Venisse
Nicolas
N
Benoit
Jean-Pierre
JP
Couet
William
W
Olivier
Jean-Christophe
JC
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000032:analysis / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000502:physiology*; D000818:Animals; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D005260:Female; D019469:Indinavir / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D049329:Nanostructures / Q000737:chemistry*; D014018:Tissue Distribution
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D002214:Capsules; D019469:Indinavir; C095122:multidrug resistance protein 3