In-vivo bioavailability and lymphatic uptake evaluation of lipid nanoparticulates of darunavir

Abstract

Darunavir is effective against wild-type and PI-resistant HIV, and has an oral bioavailability of 37%. It needs to be combined with ritonavir, which increases the bioavailability to 82%. The aim of this study was to evaluate the in-vivo efficacy of the darunavir-SLN and demonstrate lymphatic transport as a contributing pathway in increasing the drug bioavailability. The SLN was prepared by hot-homogenization technique using GMS as lipid. In-vitro drug release from SLN at the 12th hour was retarded (80.6%) compared to marketed tablet (92.6%). Ex-vivo apparent permeability of the freeze-dried SLN across everted rat intestine was 24 × 10⁻⁶ at 37 °C and 5.6 × 10⁻⁶ at 4 °C. The presence of endocytic process inhibitors like chlorpromazine and nystatin reduced it to 18.8 × 10⁻⁶ and 20.2 × 10⁻⁶, respectively, which established involvement of endocytic mechanism in the uptake of SLN. In-vivo pharmacokinetic studies on rats demonstrated increase in the AUC of SLN (26) as compared to that of marketed tablet (13.22), while the presence of lymphatic uptake inhibitor cycloheximide lowered the AUC of SLN to 17.19 which further led credence to the involvement of lymphatic uptake behind improved bioavailability. The detection of darunavir in the lymphatic fluid of the rats administered with darunavir-SLN further reinforced the conclusion of SLN being taken up by the lymphatic system.

Keywords:

• Darunavir
• endocytic uptake
• ex-vivo
• lymph fluid
• lymphatic uptake

Declaration of interest

The authors have no interest to declare.