Prediction of blood–brain barrier penetration: are we missing the point?

Martin, Iain

doi:10.1016/s1359-6446(03)02961-1

Cited by 64 publications

(45 citation statements)

References 6 publications

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“…When considering CNS penetration, perhaps the most appropriate in vivo measure is the log of the permeabilitysurface area coefficient (log PS) (Martin, 2004;Pardridge, 2004), which represents the permeability of a given solute across the brain capillary endothelium (the anatomical representation of the BBB). This measure reflects the free (unbound) extracellular solute concentrations and is most often performed following the perfusion method established by Takasato et al (1984).…”

Section: How Is Bbb Permeation Measured?mentioning

confidence: 99%

“…There is, however, little room for complacency, especially given some recent high-profile criticism leveled at log BB as an index of brain penetration (Martin, 2004;Pardridge, 2004). In particular, the fact that log BB reflects the total drug concentration in the brain rather than the free drug concentration, which crucially determines the receptor saturation by the drug, has been highlighted (Atkinson et al, 2002).…”

Section: The State Of the Artmentioning

confidence: 99%

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In Silico Predictions of Blood-Brain Barrier Penetration: Considerations to “Keep in Mind”

Goodwin¹,

Clark²

2005

J Pharmacol Exp Ther

107

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Within drug discovery, it is desirable to determine whether a compound will penetrate and distribute within the central nervous system (CNS) with the requisite pharmacokinetic and pharmacodynamic performance required for a CNS target or if it will be excluded from the CNS, wherein potential toxicities would mitigate its applicability. A variety of in vivo and in vitro methods for assessing CNS penetration have therefore been developed and applied to advancing drug candidates with the desired properties. In silico methods to predict CNS penetration from chemical structures have been developed to address virtual screening and prospective design. In silico predictive methods are impacted by the quality, quantity, sources, and generation of the measured data available for model development. Key considerations for predictions of CNS penetration include the comparison of local (in chemistry space) versus global (more structurally diverse) models and where in the drug discovery process such models may be best deployed. Preference should also be given to in vitro and in vivo measurements of greater mechanistic clarity that better support the development of structure-property relationships. Although there are numerous statistical methods that have been brought to bear on the prediction of CNS penetration, a greater concern is that such models are appropriate for the quality of measured data available and are statistically validated. In addition, the assessment of prediction uncertainty and relevance of predictive models to structures of interest are critical. This article will address these key considerations for the development and application of in silico methods in drug discovery.The main interfaces between the central nervous system (CNS) and the peripheral circulation are the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier. The surface area of the former (approximately 20 m 2 ) is several thousand times larger than the latter; thus, the BBB represents the most important barrier between the CNS and the systemic circulation (Pardridge, 2002;Graff and Pollack, 2004). There are at least two aspects of the BBB that make it a formidable barrier to candidate CNS drugs. First, in terms of its morphology, the endothelial cells of which the BBB is composed are connected by complex tight junctions, which severely limit any paracellular transport. Furthermore, a minimal level of pinocytosis and lack of significant membrane fenestrae affords an additional hindrance to the transport of hydrophilic molecules. Second, the BBB includes an array of metabolic enzyme systems and efflux transporters that constitutes a biochemical barrier to the majority of xenobiotics (de Boer et al., 2003). This combination of physical and biochemical barriers establishes the BBB endothelium as quite distinct from other endothelia, and it has been estimated to prevent the brain uptake of more than 98% of potential neurotherapeutics (Pardridge, 2002).

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Section: How Is Bbb Permeation Measured?mentioning

confidence: 99%

Section: The State Of the Artmentioning

confidence: 99%

In Silico Predictions of Blood-Brain Barrier Penetration: Considerations to “Keep in Mind”

Goodwin¹,

Clark²

2005

J Pharmacol Exp Ther

107

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“…However, although more and more compounds with high and higher total brain levels have been generated, there was no corresponding increase in the in vivo efficacy of these compounds despite excellent in vitro potency at the target mechanism. Indeed, as both in vitro potency and total brain levels are driven mainly by lipophilicity [12], many CNS drug discovery programs have ended up on a lipid escalator which, however, led them to nowhere [7b] [13].…”

mentioning

confidence: 99%

Addressing Central Nervous System (CNS) Penetration in Drug Discovery: Basics and Implications of the Evolving New Concept

Reichel

2009

Chemistry & Biodiversity

155

133

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Despite enormous efforts, achieving a safe and efficacious concentration profile in the brain remains one of the big challenges in central nervous system (CNS) drug discovery and development. Although there are multiple reasons, many failures are due to underestimating the complexity of the brain, also in terms of pharmacokinetics (PK). To this day, PK support of CNS drug discovery heavily relies on improving the blood-brain barrier (BBB) permeability in vitro and/or the brain/plasma ratio (Kp) in vivo, even though neither parameter can be reliably linked to pharmacodynamic (PD) and efficacy readouts. While increasing BBB permeability may shorten the onset of drug action, an increase in the total amount in brain may not necessarily increase the relevant drug concentration at the pharmacological target. Since the traditional Kp ratio is based on a crude homogenization of brain tissue, it ignores the compartmentalization of the brain and an increase favors non-specific binding to brain lipids rather than free drug levels. To better link exposure/PK to efficacy/PD and to delineate key parameters, an integrated approach to CNS drug discovery is emerging which distinguishes total from unbound brain concentrations. As the complex nature of the brain requires different compartments to be considered when trying to understand and improve new compounds, several complementary parameters need to be measured in vitro and in vivo, and integrated into a coherent model of brain penetration and distribution. The new paradigm thus concentrates on finding drug candidates with the right balance between free fraction in plasma and brain, and between rate and extent of CNS penetration. Integrating this data into a coherent model of CNS distribution which can be linked to efficacy will allow it to design compounds with an optimal mix in physicochemical, pharmacologic, and pharmacokinetic properties, ultimately mitigating the risk for failures in the clinic.

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“…It is possible that a relatively small redistribution from multiple tissues could lead to a marked increase in plasma concentrations. Whereas brain/plasma ratios give a useful indication of the distributional properties of a drug, cerebrospinal fluid drug levels are the preferred means, in our laboratory, of assessing central nervous system exposure with respect to pharmacological effect (Martin, 2004) and extrapolation to man. It would therefore be of interest to study the influence of CO 2 on drug levels in cerebrospinal fluid in relation to plasma.…”

Section: Fig 4 Plasma Concentrations Of Orgmentioning

confidence: 99%

The Potential Influence of CO₂, as an Agent for Euthanasia, on the Pharmacokinetics of Basic Compounds in Rodents

Angus¹,

Baker²,

Mason³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Rodent tissue distribution and pharmacokinetic studies were performed on basic compounds Org A and Org B in support of central nervous system drug discovery programs. A consistent observation from these studies was that drug concentrations in plasma obtained by cardiac puncture after CO 2 euthanasia were markedly higher compared with those from other sampling methods (serial sampling, isoflurane anesthesia, or cervical dislocation). Further investigations demonstrated that CO 2 euthanasia led to a reduction in blood pH in both rats and mice, which was not observed with the other sampling methods. The use of CO 2 euthanasia resulted in a decrease in the brain/plasma ratio of Org B, largely as a result of increased plasma concentrations. The pharmacokinetics of a basic drug, raloxifene, in rat were also influenced by sampling technique. CO 2 euthanasia before sampling, resulted in a 2-to 3-fold increase in the area under the drug concentration-time curve, a decrease in plasma clearance, and a decrease in the steady-state volume of distribution compared with isoflurane anesthesia. It is proposed that a decrease in the pH of blood relative to that of other tissues, as a consequence of CO 2 exposure, results in a redistribution of basic compounds out of the tissues, leading to higher concentrations in plasma.

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Prediction of blood–brain barrier penetration: are we missing the point?

Cited by 64 publications

References 6 publications

In Silico Predictions of Blood-Brain Barrier Penetration: Considerations to “Keep in Mind”

In Silico Predictions of Blood-Brain Barrier Penetration: Considerations to “Keep in Mind”

Addressing Central Nervous System (CNS) Penetration in Drug Discovery: Basics and Implications of the Evolving New Concept

The Potential Influence of CO₂, as an Agent for Euthanasia, on the Pharmacokinetics of Basic Compounds in Rodents

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Prediction of blood–brain barrier penetration: are we missing the point?

Cited by 64 publications

References 6 publications

In Silico Predictions of Blood-Brain Barrier Penetration: Considerations to “Keep in Mind”

In Silico Predictions of Blood-Brain Barrier Penetration: Considerations to “Keep in Mind”

Addressing Central Nervous System (CNS) Penetration in Drug Discovery: Basics and Implications of the Evolving New Concept

The Potential Influence of CO2, as an Agent for Euthanasia, on the Pharmacokinetics of Basic Compounds in Rodents

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The Potential Influence of CO₂, as an Agent for Euthanasia, on the Pharmacokinetics of Basic Compounds in Rodents