ABSTRACT
The penetration of drugs into the central nervous system is a composite of both the rate of drug uptake across the blood-brain barrier and the extent of distribution into brain tissue compartments. Clinically, positron emission tomography (PET) is the primary technique for deriving information on drug biodistribution as well as target receptor occupancy. In contrast, rodent models have formed the basis for much of the current understanding of brain penetration within pharmaceutical Drug Discovery. Linking these two areas more effectively would greatly improve the translation of candidate compounds into therapeutic agents. This paper examines two of the major influences on the extent of brain penetration across species, namely plasma protein binding and brain tissue binding. An excellent correlation was noted between unbound brain fractions across species (R(2) > 0.9 rat, pig, and human, n = 21), which is indicative of the high degree of conservation of the central nervous system environment. In vitro estimates of human brain-blood or brain-plasma ratios of marketed central nervous system drugs and PET tracers agree well with in vivo values derived from clinical PET and post-mortem studies. These results suggest that passive diffusion across the blood-brain barrier is an important process for many drugs in humans and highlights the possibility for improved prediction of brain penetration across species.
Subject(s)
Blood-Brain Barrier/metabolism , Central Nervous System Agents/pharmacokinetics , Animals , Drug Discovery , Humans , Positron-Emission Tomography , Rats , Rats, Sprague-Dawley , SwineSubject(s)
Community Networks , Ethnicity , Power, Psychological , Race Relations , Religion , Social Problems , Africa/ethnology , Black People/education , Black People/ethnology , Black People/history , Black People/legislation & jurisprudence , Black People/psychology , Brazil/ethnology , Community Networks/economics , Community Networks/history , Community Networks/legislation & jurisprudence , Ethnicity/education , Ethnicity/ethnology , Ethnicity/history , Ethnicity/legislation & jurisprudence , Ethnicity/psychology , History, 16th Century , Humans , Indians, South American/education , Indians, South American/ethnology , Indians, South American/history , Indians, South American/legislation & jurisprudence , Indians, South American/psychology , Prejudice , Race Relations/history , Race Relations/legislation & jurisprudence , Race Relations/psychology , Religion/history , Residence Characteristics , Social Dominance , Social Problems/economics , Social Problems/ethnology , Social Problems/history , Social Problems/legislation & jurisprudence , Social Problems/psychologyABSTRACT
A reversed-phase high-performance liquid chromatographic (HPLC) assay using ultraviolet spectrophotometric detection has been developed for the determination of the concentration of 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline (I) in rat, dog and human plasma. Prior to analysis, the protein in plasma samples was precipitated with acetonitrile containing 3-butyryl-4-(2-methylphenylamino)-8-methoxyquinoline to act as an internal standard. The supernatant layer was injected onto the HPLC column with no further clean-up. The assay requires 200 microliters of plasma and is precise and accurate within the range 25-1000 ng/ml. The mean within-run and between-run coefficients of variation were < 6% at 25 ng/ml and greater concentrations. The mean accuracy of quality control standards was generally within +/- 5% of the nominal concentration. Recovery of I and internal standard from plasma was approximately 100% over the entire assay range irrespective of species.
