Tug-of-war

The aim of discussing basic #pharmacokinetics #concept #9 is to appreciate how the differential binding of drug to plasma protein and tissue components defines the apparent volume of drug distribution (V).

As a recap, plasma protein binding is measured based on its fraction unbound (fu) in plasma ( post #8; https://www.dhirubhai.net/feed/update/urn:li:activity:6994091050717896704/). Similarly, the degree of tissue binding is defined as fraction unbound of drug in tissue (fuT). Both fu and fuT are independent as drug interacts with plasma protein and tissue components differently.

V is an important pharmacokinetic parameter that informs the extent of drug distribution in our body. The larger the V, the more widely the drug is distributed to tissue and vice versa. A larger V also contributes to longer biological half-life (future discussion). V is poignantly defined as the fluid volume in which a drug seems to be distributed to account for its plasma concentration. The term ‘apparent’ reminds us that V is not physiological. For instance, V of morphine is more than 200 L where the total body water (TBW) volume of a 70 kg man is only 42 L. A question arises: why V of some drugs are greater than TBW volume?

At distribution equilibrium (post #7), unbound plasma and tissue concentrations of drug are equal (Cu = CuT; no active transport), and V of a drug is defined by (1) physiological fluid volumes (Vp and VT), (2) fu and (3) fuT where V = Vp + VT*(fu/fuT). From this relationship, V increases when fu increases and decreases when fuT increases. Hence, for some drugs (e.g. propranolol), when fu increases (e.g. due to change in plasma protein concentration), V increases. So why is V apparent? This is because the fu/fuT ratio can be significantly greater than 1! For example, fu and fuT of amiodarone are 0.04 and 0.0002, respectively. Consequently, fu/fuT is 200 and V becomes close to 7000L! This is similar to tug-of-war where teams pull on opposite end of the ropes. In the case of a drug with a larger V, it is being ‘tugged’ to a greater extent into the tissue compartment as compared to the plasma compartment.

In conclusion, drugs have vastly different V spanning from 20 L for warfarin to 40,000 L for quinacrine. This is due to the differential interactions of drugs with plasma proteins versus tissue components. V is an important parameter that defines the pharmacokinetics and pharmacology of drugs (nutraceuticals) and understanding its apparentness becomes important. If you like to learn more about the basic concepts in?#pharmacokinetics, let me know and follow my future posts.

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