Progress in Brain Penetration Evaluation in Drug Discovery and Development

Abstract

This review discusses strategies to optimize brain penetration from the perspective of drug discovery and development. Brain penetration kinetics can be described by the extent and time to reach brain equilibrium. The extent is defined as the ratio of free brain concentration to free plasma concentration at steady state. For all central nervous system (CNS) drug discovery programs, optimization of the extent of brain penetration should focus on designing and selecting compounds having low efflux transport at the blood-brain barrier (BBB). The time to reach brain equilibrium is determined by both BBB permeability and brain tissue binding. Rapid brain penetration can be achieved by increasing passive permeability and reducing brain tissue binding. Although many drug transporters have been identified at the BBB, the available literature demonstrates only the in vivo functional importance of P-glycoprotein (P-gp) in limiting brain penetration of its substrates. Drug-drug interactions mediated by P-gp at the BBB are possible due to inhibition or induction of P-gp. For newly identified drug transporters at the BBB, more research is needed to reveal their in vivo significance. We propose the following strategies for addressing drug transporters at the BBB. 1) Drug discovery screens should be used to eliminate good P-gp substrates for CNS targets. Special consideration could be given to moderate P-gp substrates as potential CNS drugs based on a high unmet medical need and the presence of a large safety margin. 2) Selection of P-gp substrates as drug candidates for non-CNS targets can reduce their CNS-mediated side effects.Brain is separated from the systemic circulation by two barriers: the blood-brain barrier (BBB) and the blood-cerebrospinal-fluid barrier (BCSFB). The BBB is composed of cerebral endothelial cells that differ from those in the rest of the body by the presence of extensive tight junctions, absence of fenestrations, and sparse pinocytotic vesicular transport. The BCSFB is formed by a continuous layer of polarized epithelial cells that line the choroid plexus. The BBB and BCSFB exhibit very low paracellular permeability and express multiple drug transporters. These characteristics restrict the entry of hydrophilic compounds or efflux transport substrates into brain (Davson and Segal, 1995). In this review, we will summarize recent published data relevant to assess drug brain penetration and present the authors' opinions on how to effectively address BBB issues in drug discovery and development.

Unbound Drug Concentration in Brain Homogenate and Cerebral Spinal Fluid at Steady State as a Surrogate for Unbound Concentration in Brain Interstitial Fluid

“…Importantly for ethical reasons, this method cannot be used routinely to measure the interstitial fluid concentration in clinical trials, although it has been used to monitor glucose metabolism such as lactate and pyruvate ratio as a marker for ischemia in brain trauma patients in a few lifethreatening situations (Benjamin et al, 2004;Hillered et al, 2006;Chaurasia et al, 2007;Helmy et al, 2007). Because of these limitations, several alternative methods, such as brain homogenate, brain slice, and cerebral spinal fluid (CSF), have been proposed and used to estimate brain unbound drug concentrations (Liu et al, 2008). A brain homogenate method has been proposed as a surrogate approach to estimate brain unbound concentration (C ub ) (Kalvass and Maurer, 2002).…”

“…Unbound plasma concentration (C up ) has been used to represent the unbound concentration in tissue (Wilkinson, 2001). Because the brain is separated from the plasma by the blood-brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB), C up may not represent the interstitial fluid concentration (Davson and Segal, 1995;Hammarlund-Udenaes et al, 2008;Liu et al, 2008).…”

“…Unbound plasma concentration (C up ) has been used to represent the unbound concentration in tissue (Wilkinson, 2001). Because the brain is separated from the plasma by the blood-brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB), C up may not represent the interstitial fluid concentration (Davson and Segal, 1995;Hammarlund-Udenaes et al, 2008;Liu et al, 2008).Microdialysis has been considered as a standard approach to measure interstitial fluid concentration (C m ) (Joukhadar and Müller, 2005;Chaurasia et al, 2007). Although this technique has been developed for more than 2 decades, it is primarily used for determination of neurotransmitters and not drug concentrations in the brain.…”

The Blood-Brain Barrier in Epilepsy

“…LAT1 mediates brain uptake of L-DOPA that is used in Parkinson's disease (Del Amo et al, 2008). LAT1 has also been reported to transport the AEDs gabapentin and pregabalin across the blood-brain barrier into the brain (Del Amo et al, 2008;Liu et al, 2008;Su et al, 1995). Whether LATs are affected in epilepsy is unknown.…”

“…Most information on transporter regulation is available for P-gp, where signalling pathways have been shown to be present in various tissues (liver, kidney, intestine; (Ho & PiquetteMiller, 2006;Nawa et al, 2010;Thevenod et al, 2000). They also involve various signalling molecules: inflammatory mediators including TNF-, ET-1, IL1-, IL-6, NO; COX-2 (Dixit et al, 2005;Goralski et al, 2003;Nawa et al, 2010;Patel et al, 2002;Poller et al, 2010;Sukhai et al, 2001;Von Wedel-Parlow et al, 2009), nuclear receptors PXR, CAR, AhR, and GR (Bauer et al, 2004;Bauer et al, 2007;Geick et al, 2001;Narang et al, 2008;Wang et al, 2011;Wang et al, 2010), protein kinase C (Bauer et al, 2007;Chambers et al, 1990a;Chambers et al, 1990b;Hartz et al, 2004;Miller et al, 1998;Rigor et al, 2010), and NFkB (Bauer et al, 2007;Bentires-Alj et al, 2003;Kim et al, 2011;Liu et al, 2008;Thevenod et al, 2000;Yu et al, 2008). These pathways have been found in several diseases including Alzheimer's disease, HIV, and diabetes (Hartz et al, 2010;Hayashi et al, 2006;Nawa et al, 2010).…”