Central nervous system distribution kinetics of indinavir in rats

Abstract

The central nervous system (CNS) distribution kinetics of indinavir were extensively evaluated using a combinational in-vivo model comprising the integration plot method (a single-passage approach) and neuropharmacokinetic method (a multiple-passage approach). A 5 mg kg−1 dose of indinavir was administered intravenously to rats. Blood and cerebrospinal fluid (CSF) samples and whole brain were collected from the animals at specified time points and the drug concentration in each sample was determined using a high-performance liquid chromatography method. For the neuropharmacokinetic study, the simultaneous plasma, CSF and brain concentrations were fitted to an integrated model, which resulted in the estimation of the influx (Kin) and efflux (Kout) rate constants of the drug to/from CSF and brain parenchyma. The integration plot method involved plotting the brainplasma or CSF-plasma concentration ratios (Kp,app) against AUC0r̊t/Cp(t), and estimating the uptake clearance of the drug by brain/CSF from the slope of the initial linear portion of the plot. The Kin and Kout values of the drug to/from CSF were estimated to be 2.42 times 10−2 and 13.26 times 10−2min−1, respectively, and the corresponding values for brain parenchyma were 1.02 times 10−2 and 1.32 times 10−2 min−1, respectively. The uptake clearances of indinavir by CSF and brain parenchyma were 8.89 and 8.38 μLmin−1 g−1, respectively. The permeability surface area products of the drug for the blood-brain barrier and blood-CSF barrier were estimated as 1.05 times 10−2 and 2.45 times 10−2 mL min−1 g−1, respectively. The estimated kinetic parameters indicated limited CNS entry of the drug because of the limited blood-brain barrier permeability and the efficient drug efflux from CNS, particularly from CSF.