This work examines the inter-relationship between the unbound drug fractions in blood and brain homogenate, passive membrane permeability, P-glycoprotein (Pgp) efflux ratio, and log octanol/water partition coefficients (cLogP) in determining the extent of central nervous system (CNS) penetration observed in vivo. The present results demonstrate that compounds often considered to be Pgp substrates in rodents (efflux ratio greater than 5 in multidrug resistant Madin-Darby canine kidney cells) with poor passive permeability may still exhibit reasonable CNS penetration in vivo; i.e., where the unbound fractions and nonspecific tissue binding act as a compensating force. In these instances, the efflux ratio and in vitro blood-brain partition ratio may be used to predict the in vivo blood-brain ratio. This relationship may be extended to account for the differences in CNS penetration observed in vivo between mdr1a/b wild type and knockout mice. In some instances, cross-species differences that might initially seem to be related to differing transporter expression can be rationalized from knowledge of unbound fractions alone. The results presented in this article suggest that the information exists to provide a coherent picture of the nature of CNS penetration in the drug discovery setting, allowing the focus to be shifted away from understanding CNS penetration toward the more important aspect of understanding CNS efficacy.Within the modern drug discovery paradigm, drug metabolism and pharmacokinetics (DMPK) play an integral role in the process of compound selection and progression. Much of the impact of DMPK has been caused by its transformation from a largely descriptive discipline to that of a predictive science, fuelled by advances in bioanalysis and in vitro techniques. Hence discovery DMPK provides a powerful means for assessing the risks of taking potential assets into development.Nevertheless, the development of molecules targeted at the central nervous system (CNS) remains a significant challenge caused by the increased regulation and protection afforded to the brain over other organs of the body. The major knowledge gaps are 1) understanding the physicochemical features that determine CNS penetration, 2) understanding the impact of the blood-brain barrier (BBB) on CNS uptake, and 3) providing a coherent measure of CNS penetration that can be related to drug efficacy. Regarding the latter point, although it is important to develop a link between the pharmacokinetics of a molecule and the biophase, arguably the critical issue is one of sufficient access of free drug to the requisite site of action.Numerous models and measures of CNS uptake are available to assist in the search for centrally active agents. In situ brain perfusion techniques have highlighted the good correlation between increasing lipophilicity and CNS permeability. Polar drugs that are subject to paracellular absorption such as atenolol (logD oct,7.4 Ϫ2.1; Artursson, 1990) and sumatriptan (logD oct,7.4 Ϫ1.5;Pascual and Munoz, 2005) show...

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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.

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1. The ability of hepatic microsomal metabolic stability assessments to predict in vivo clearance in rat has been retrospectively evaluated for 1,163 compounds from 48 programmes of chemistry. Using a simple binary classification system, the in vivo clearances of approximately 64% of the compounds were correctly classified. 2. About 24% of compounds were metalbolically stable yet had clearance greater than half of liver blood flow in vivo. This might be expected as microsomes only contain a limited number of fully functioning drug-metabolizing enzymes and cannot be expected to account for extrahepatic or non-metabolic clearance processes. 3. About 13% of compounds had in vivo clearances of less than half liver blood flow despite being classified as metabolically unstable. Despite overcoming metabolic instability, these compounds had other undesirable properties and were generally more highly bound to plasma proteins, had smaller volumes of distribution (and shorter half-lives despite their clearance) and were more inhibitory against the major human cytochrome P450s. 4. Taking plasma protein binding into consideration reduced the proportion of misclassified low-clearance compounds but did not improve the overall success appreciably. Somewhat surprisingly, human microsomes were nearly as effective as rat microsomes at classifying rat in vivo clearance.