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 (K(in)) and efflux (K(out)) rate constants of the drug to/from CSF and brain parenchyma. The integration plot method involved plotting the brain-plasma or CSF-plasma concentration ratios (K(p, app)) against AUC(0-->t)/C(p(t)), and estimating the uptake clearance of the drug by brain/CSF from the slope of the initial linear portion of the plot. The K(in) and K(out) values of the drug to/from CSF were estimated to be 2.42 x 10(-2) and 13.26 x 10(-2)min(-1), respectively, and the corresponding values for brain parenchyma were 1.02 x 10(-2) and 1.32 x 10(-2) min(-1), respectively. The uptake clearances of indinavir by CSF and brain parenchyma were 8.89 and 8.38microL min(-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 x 10(-2) and 2.45 x 10(-2) mLmin(-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.

Lack of Evidence for Involvement of P-Glycoprotein in Brain Uptake of the Centrally Acting Analgesic, Tramadol in the Rat

“…As an alternative possible approach, the integration plot analysis described by Hamidi (2007) was applied for graphic estimation of the uptake clearance of tramadol by the rat brain parenchyma (27). Integration of Eq.…”

“…Therefore, by plotting the ratios of the drug concentrations in brain samples at time t to the simultaneous plasma concentrations against the ratios of area under the plasma concentrationtime curve from 0 to t to the corresponding plasma concentrations (AUC 0→t /C p(t) ) (integration plot), a line will be obtained at the early time intervals, whose slope and y-intercept illustrate the apparent tissue uptake clearance and the volume of plasma in tissue vasculature per unit mass of the tissue, respectively (27).…”

An Automated Customizable Live Web Crawler for Curation of Comparative Pharmacokinetic Data: An Intelligent Compilation of Research-Based Comprehensive Article Repository

“…Table 5. Crossref information retrieval for some of the selected DOIs 10.1002/bmc.4728 [49], 10.1111/jvp.13054 [51], 10.1111/jphp.13353 [50], 10.1111/jphp.12275 [52], and 10.1211/jpp.59.8.0004 [53] to obtain the full-text (XML, PDF) links. The remaining DOIs, which are stored in the CSV file called the unsuccessful or incomplete list, are handled separately to download the HTML or PDF file types using a different API called the Selenium web driver with its Chrome driver option facilitated through Python [26].…”

“…Figure 5. A portion of the full-text articles for the doi 10.1002/bmc.4728[49] (A) XML[50], and (B) PDF[51], and doi 10.1111/jphp.13353[53] (C) XML[50], and (D) PDF[53] file types retrieved from Crossref APIs are shown here.…”