Comparative pharmacokinetic evaluation of lopinavir and lopinavir-loaded solid lipid nanoparticles in hepatic impaired rat model.
OBJECTIVE
Drug-induced hepatotoxicity is a major cause of concern in patients receiving HIV/TB co-treatment. Lopinavir (LPV), an anti-HIV drug, shows poor plasma exposure due to hepatic first-pass metabolism. In this study, we investigated the effect of hepatotoxicity on pharmacokinetics of free LPV and LPV-loaded solid lipid nanoparticles (LPV SLNs) in male Wistar rats.


METHODS
Hepatic impairment model in rats was developed by injecting CCl4(i.p., 2 ml/kg). Comparative pharmacokinetic (n = 5) and tissue distribution studies (n = 3) were conducted following oral administration (20 mg/kg) of free LPV and LPV SLNs in normal and hepatic impaired rats. Isolated perfused liver (IPL) model (n = 3) and cycloheximide intervened lymphatic uptake studies (n = 3) were conducted to appreciate disposition pattern of LPV.


RESULTS
In contrary to free LPV, pharmacokinetic results demonstrated no significant (P > 0.05) difference in drug plasma profile of LPV SLNs in normal and impaired rats. IPL model demonstrated trivial role of liver in disposition of LPV SLNs. Tissue distribution studies of SLNs showed higher (P < 0.05) LPV accumulation in lymphoidal organs. Pretreatment of cycloheximide significantly (P < 0.05) reduced AUC and Cmaxof LPV SLNs.


CONCLUSIONS
From the results, we conclude that unlike conventional formulations of LPV, disposition characteristics of LPV SLNs were similar both in normal and hepatic impaired rats.
Department of Pharmacy, BITS-Pilani, Hyderabad Campus, Hyderabad, Telangana, India.
Punna Rao
http://orcid.org/0000-0002-3728-353X
PR
Ravi
Novartis Healthcare, Hyderabad, Telangana, India.
Rahul
R
Vats
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D004195:Disease Models, Animal; D008055:Lipids / Q000737:chemistry; D008107:Liver Diseases / Q000503:physiopathology*; D061466:Lopinavir / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D053758:Nanoparticles; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D019380:Anti-HIV Agents; D008055:Lipids; D061466:Lopinavir

HIV
; hepatic impairment; lopinavir; pharmacokinetic studies; solid lipid nanoparticles