TGIF

TGIF! Let’s continue to discuss basic #pharmacokinetics #concept #8

Previously, we learned that the total tissue drug concentration may be higher or lower than total blood drug concentration at tissue distribution equilibrium. As a recap, equilibrium does not mean equal (https://www.dhirubhai.net/feed/update/urn:li:activity:6991588738929741824/).

Question is why? This is because the binding of drug to plasma protein is independent of its binding to tissue protein. Today, we shall discuss the former.

Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent. One common plasma protein that binds drug is albumin. In plasma, the drug molecule can exist as free unbound drug or albumin-bound drug. This is similar to people who are walking (free) versus those who are riding a bus (bound). The degree of binding is defined as fraction unbound (fu) which has limiting values of 0 and 1. When the fu is low (e.g. 0.01), the drug is highly bound to plasma protein. When the fu is high (e.g. 0.99), the drug is minimally bound to plasma protein. Essentially, fu is the ratio of unbound drug concentration (Cu) to total plasma drug concentration (C) where fu = Cu/C.

Based on free-drug hypothesis, it is the free unbound drug that acts on a drug target to produce the medicinal effect (pharmacology). Hence, a question arises, should we measure Cu or C in pharmacokinetic studies?

At the therapeutic concentration of most drugs, fu is relatively constant at a given protein concentration and independent of drug concentration. While Cu should principally be measured for correlation with pharmacology, C can be more practically measured instead, since Cu and C will increase and decrease in tandem when fu is constant. Hence, both Cu and C correlate with drug effect. This explains why C is commonly and more efficiently measured in preclinical and clinical pharmacokinetic studies (note: measuring Cu is relatively expensive and tedious). There are of course exceptions where fu is not a constant (e.g. when plasma protein concentration changes in diseases) which would not be elaborated here.

In conclusion, drug moves around our body by binding to plasma protein (fascinatingly similar to people travelling around in vehicles) but it is the free drug that defines the pharmacology (similar to people getting the work done and not the vehicles). If you like to learn more about the basic concepts in?#pharmacokinetics, let me know and follow my future articles.

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