Abstract
Drug-protein binding plays a key role in determining the pharmacokinetics of a drug. The distribution and protein binding ability of a drug changes over a lifetime, and are important considerations during pregnancy and lactation. Although proteins are a significant fraction in plasma composition, they also exist beyond the bloodstream and bind with drugs in the skin, tissues or organs. Protein binding influences the bioavailability and distribution of active compounds, and is a limiting factor in the passage of drugs across biological membranes and barriers: drugs are often unable to cross membranes mainly due to the high molecular mass of the drug-protein complex, thus resulting in the accumulation of the active compounds and a significant reduction of their pharmacological activity. This review describes the consequences of drug-protein binding on drug transport across physiological barriers, whose role is to allow the passage of essential substances—such as nutrients or oxygen, but not of xenobiotics. The placental barrier regulates passage of xenobiotics into a fetus and protects the unborn organism. The blood–brain barrier is the most important barrier in the entire organism and the skin separates the human body from the environment.
Highlights
Following absorption from the gastrointestinal system or direct infusion into bloodstream, a drug can bind with plasma proteins
The degree of plasma protein binding is governed by two variables, these being the unbound fraction of the drug in plasma (fu,p) and the percentage of plasma protein binding (PPB%), as given below in Eqs. 1 and 2 [3]: unbound drug concentration in plasma fu,p =
Binding with human serum albumin (HSA) and alpha1-acid glycoprotein (AAG) macromolecules affects the pharmacokinetic properties of pharmacologically-active compounds by decreasing their bioavailability and slowing their passage across biological membranes and barriers [32–34]; proteins themselves hardly penetrate through the cell membranes [35–37]
Summary
Following absorption from the gastrointestinal system or direct infusion into bloodstream, a drug can bind with plasma proteins. The ability of a molecule to cross the membrane depends on various factors including molecular weight, lipophilicity, ionisation state, the concentration on both sides of the barrier and protein binding [26, 27]. Binding with HSA and AAG macromolecules affects the pharmacokinetic properties of pharmacologically-active compounds by decreasing their bioavailability and slowing their passage across biological membranes and barriers [32–34]; proteins themselves hardly penetrate through the cell membranes [35–37].
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