Binding of Drugs to Plasma Proteins

 Drug molecules may bind to plasma proteins (usually albumin). Bound drugs are pharmacologically inactive; only the free, unbound drug can act on target sites in the tissues, elicit a biologic response, and be available to the processes of elimination.

 [Note: Hypoalbuminemia may alter the level of free drug]

A. Binding capacity of albumin

The binding of drugs to albumin is reversible and may show low capacity (one drug molecule per albumin molecule) or high capacity (a number of drug molecules binding to a single albumin molecule). Drugs can also bind with varying affinities. Albumin has the strongest affinities for anionic drugs (weak acids) and hydrophobic drugs. Most hydrophilic drugs and neutral drugs do not bind to albumin.

 [Note: Many drugs are hydrophobic by design, because this property permits absorption after oral administration.]

 B. Competition for binding between drugs

When two drugs are given, each with high affinity for albumin, they compete for the available binding sites. The drugs with high affinity for albumin can be divided into two classes, depending on whether the dose of drug (the amount of drug found in the body under conditions used clinically) is greater than, or less than, the binding capacity of albumin (quantified as the number of millimoles of albumin multiplied by the number of binding sites)

 Figure 1.13). 

1. Class I drugs: 

If the dose of drug is less than the binding capacity of albumin, then the dose/capacity ratio is low. The binding sites are in excess of the available drug, and the bound-drug fraction is high. This is the case for Class I drugs, which include the majority of clinically useful agents. 

2. Class II drugs: 

These drugs are given in doses that greatly exceed the number of albumin binding sites. The dose/capacity ratio is high, and a relatively high proportion of the drug exists in the free state, not bound to albumin.

 3. Clinical importance of drug displacement: 

This assignment of drug classification assumes importance when a patient taking a Class I drug, such as warfarin, is given a Class II drug, such as a sulfonamide antibiotic. Warfarin is highly bound to albumin, and only a small fraction is free. This means that most of the drug is sequestered on albumin and is inert in terms of exerting pharmacologic actions. If a sulfonamide is administered, it displaces warfarin from albumin, leading to a rapid increase in the concentration of free warfarin in plasma, because almost 100 percent is now free, compared with the initial small percentage.

 [Note: The increase in warfarin concentration may lead to increased therapeutic effects, as well as increased toxic effects, such as bleeding.]

 C. Relationship of drug displacement to Vd 

The impact of drug displacement from albumin depends on both the Vd and the therapeutic index  of the drug. If the Vd is large, the drug displaced from the albumin distributes to the periphery, and the change in free-drug concentration in the plasma is not significant. If the Vd is small, the newly displaced drug does not move into the tissues as much, and the increase in free drug in the plasma is more profound. If the therapeutic index of the drug is small, this increase in drug concentration may have significant clinical consequences. 

[Note: Clinically, drug displacement from albumin is one of the most significant source of drug interaction ]

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