Pharmacokinetics, tissue distribution and relative bioavailability of isoniazid-solid lipid nanoparticles

Low levels of isoniazid gain access into plasma following oral administration due to its high aqueous solubility, poor permeability and rapid and extensive hepatic metabolism. Further, a small t(1/2) of 1-4 h indicates its short stay in plasma and the need for repetitive or high doses which may subsequently result in hepatotoxicity and neurotoxicity associated with its use. Isoniazid-solid lipid nanoparticles (SLNs) were prepared to achieve improved bioavailability and prolonged effect, thus minimizing pulsatile plasma concentrations (and associated side effects at peak plasma concentrations). Developed SLNs showed high entrapment efficiency (69%) and small size (d(90) 48.4 nm) such that they are expected to bypass reticulo-endothelial system (RES) pickup resulting in prolonged circulation times and since liver is the major site of metabolism of isoniazid, RES avoidance will reduce its elimination from the body. Single dose (25 mg/kg BW) oral pharmacokinetic studies were performed in plasma and various tissues of rats. A significant improvement (p < 0.001) in relative bioavailability in plasma (6 times) and brain (4 times) was observed after administration of isoniazid-SLNs with respect to the free drug solution at the same dose. Insignificant changes in liver concentration coupled with bypass of first pass metabolism and slow release of isoniazid (60%, in 24 h) indicate low incidence of hepatotoxicity. Isoniazid-SLNs showed a 3 times higher LD50. (C) 2012 Elsevier B. V. All rights reserved.