Plasma protein binding
The plasma contains several soluble proteins that circulate within the bloodstream and that have roles in, for example, the transport of a variety of endogenous molecules around the body, and in the maintenance of blood volume through osmotic effects. Some of these proteins are also able to bind many drugs, reversibly and with low affinity. Serum albumin is present in healthy adults within a range between 500 and 720 µM, with each protein able to bind two acidic or neutral drug molecules. Alpha-1-acid glycoprotein is typically present within a lower range, between 25 and 50 µM, and each protein can bind one basic drug molecule. As such, these proteins provide reservoirs within which up to 50 µM of basic drug, or up to 1.4 mM of acidic or neutral drug, may be sequestered temporarily within the plasma.
Since a drug that is bound to a plasma protein can not cross a cell membrane (in order to distribute to tissues), or interact with any other protein (such as a metabolic enzyme or a renal transporter), or be filtered at Bowman’s capsule, then the degree to which a drug is bound to plasma proteins can have a significant impact on pharmacokinetic and therapeutic behaviour of the drug.
Drugs are typically present in large excess with respect to the concentration of their target proteins, such that when free target proteins are “depleted” due to drug binding, there is a negligible drop in the concentration of free drug. In contrast, plasma proteins are typically present in large excess with respect to the concentration of drug in the blood stream, such that association of drug with the proteins is accompanied by a depletion of the free drug, rather than by a depletion of plasma protein binding sites.
In simply qualitative terms, drugs that bind more extensively to plasma proteins may have a significant portion of the administered dose bound to plasma proteins and therefore much of the drug may still be present (as bound drug) in the plasma. This can lead to a very low value (8-12 litres) for the volume of distribution of a drug with high plasma protein binding, although it is also possible for a drug that is highly bound to plasma proteins also to be very lipophilic, with the result that the volume of distribution might still be quite high.
In more quantitative terms, the affinities of drugs for binding to plasma proteins tend to be relatively low (in the micromolar range), but due to the high concentrations of plasma proteins present, it is common for a reasonable proportion of the plasma content of a drug to be bound. Unlike the mathematics of drugs binding to receptors, governed by the Hill-Langmuir equation, where binding of drug to receptors causes a negligible fall in the concentration of unbound drug, the opposite is true for plasma protein binding; indeed, this is the whole point – binding of drugs to plasma proteins depletes the unbound concentration of drug, and anything that alters the degree of plasma protein binding will impact the free concentration of drug, and consequently the pharmacokinetic behaviour and therapeutic effects of the drug. When a drug administered at a dose at the lower end of its therapeutic dose range results in occupation of a high proportion of plasma protein binding sites, a higher therapeutic dose may lead to saturation of those sites and a disproportionate increase in free (unbound) drug in the plasma, and therefore in the tissues. This (perhaps unexpected, but entirely predictable) increase in the concentration of free drug – referred to as dose-dependent kinetics or non-linear kinetics – can result in on-target and off-target side effects.
Given that it is the unbound fraction of the drug that is able to have a therapeutic effect (including causing side-effects), then administering two drugs that both bind extensively to plasma proteins can result in competition for binding and less binding of both drugs to the plasma proteins, possibly leading to elevated concentrations of one or both drugs. This may lead to side-effects.
As well as competition with other drugs, plasma proteins change in a number of physiological and pathophysiological conditions such as age, malnutrition, renal or hepatic disease, infections and inflammatory conditions.
Plasma protein binding is reversible, just like binding of drugs to other proteins. As such, it is possible, for example, for a drug that is quite highly bound to plasma proteins still to be metabolised very extensively in the liver. As blood passes through the liver, unbound drug is rapidly metabolised, so some bound drug dissociates to re-establish the equilibrium, and this unbound drug is then rapidly metabolised, and so on. By the time the blood exits the liver, much of the drug may have been “stripped off” the plasma proteins and metabolised, even though a significant portion of the drug was highly plasma protein bound initially. The more slowly blood passes through the liver, the greater the time during which drug can dissociate from plasma proteins and be exposed to drug metabolising enzymes; this is why the hepatic extraction ratio for a drug depends in part upon hepatic blood flow, QH.
