The Role of Plasma Protein Binding in Drug Delivery to Brain
At a glance
Introduction
Drug delivery to brain is limited by the blood-brain barrier (BBB) (i.e., neurovascular unit) which markedly impacts treatment for stroke. Among the various factors affecting BBB permeability and limiting drug delivery to the brain, one of the least understood is the role of plasma protein binding. This process encompasses a complex interaction involving cerebral blood flow, the glycocalyx of brain capillaries, and the plasma membrane, alongside the levels of free and bound drugs in the capillary circulation.
It is important to know how these factors interact to make better drug delivery strategies for stroke. Scientists are trying new tricks like altering the formulation of drugs to lessen protein binding or nanoparticles to open up the BBB for better therapy. Understanding more about plasma protein binding and how it influences the delivery of drugs is the way forward for conquering BBB in stroke treatment and other neurological disorders.
Ace Therapeutics offers a variety of in vitro binding assays including plasma protein binding (PPB), brain tissue binding, and plasma partitioning (BPP). Protocols can be flexibly adapted to specific customer requirements.
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Drug-protein Binding
In the blood, drugs are present in the unbound form but may also be bound to plasma proteins and erythrocytes. The main proteins responsible for plasma binding are human serum albumin (HSA) and alpha-1-acid glycoprotein (AAG). This binding is reversible and equilibrium is achieved within a few hours of administration.
The structure and properties of the drug determine the extent of plasma protein binding in the sense of the general process. Lipophilicity (logP) and acid–base properties have a significant correlation with binding. Hydrophobic and acidic drugs bind preferably to HSA, while AAG connects with the basic ones. Binding can also increase the solubility of compounds, especially hydrophobic ones. Furthermore, binding to these proteins provides a protective effect against oxidation, reduces toxicity, and extends the compounds' half-lives. Generally, drugs that are extensively bound to plasma proteins demonstrate lower first-pass metabolism. The volume of distribution is influenced by protein binding as well. It decreases for drugs that are primarily bound in plasma and increases for those that accumulate in tissues. Additionally, when drugs have a higher affinity for plasma protein binding sites, they can displace those with a lower affinity, which may lead to an unintended increase in the concentration of the free, unbound drug fraction.
Plasma protein binding levels also depend on the surrounding environment, such as temperature or pH. They can alter the ionization state of a compound.
Pharmacokinetics of Brain Delivery and Distribution of Drugs
The free drug hypothesis suggests that unbound concentrations in the brain are pharmacologically active. This implies that plasma protein binding plays a bystander role in the distribution and pharmacodynamic homeostasis results because it does not affect the extent to which unbound drug concentrations are transported across the BBB. However, since total plasma concentrations are often used as a reference in pharmacokinetic studies, estimating plasma protein binding is essential for the rational interpretation of pharmacokinetic data, especially when relating results to drug pharmacodynamics.
Unbound drug molecules equilibrate across the BBB with those in the brain's interstitial fluid (ISF), and this equilibration also occurs within the interstitial space and across cell membranes. Multiple equilibration processes happen simultaneously, with the slowest process determining the rate at which steady state is achieved between blood and brain concentrations. For drugs with low BBB permeability, this slowest step is often the transport across the BBB or diffusion within brain tissue.
The active influx and efflux transport mechanisms at the BBB further complicate brain pharmacokinetics. The P-glycoprotein efflux transporter plays a significant role in lowering brain drug concentrations by preventing entry and extruding drugs already within BBB endothelial cells back into the bloodstream. The impact on brain concentration-time profiles depends on which of these functions is more dominant. Additionally, some compounds may be transported from the brain ISF into endothelial cells via abluminal transporters and then from the BBB back to the blood through luminal transporters. This coordinated action of transporters at both membranes of the BBB can either decrease or increase the brain concentrations of certain drugs.
Fig.1. A schematic drawing of the equilibration of drug concentrations among blood, brain and CSF. (Hammarlund-Udenaes, et al., 2008)
- Hammarlund-Udenaes, M., et al. (2008). On the rate and extent of drug delivery to the brain. Pharmaceutical research, 25, 1737-1750.
