HOWwellareDRUGSDISTRIBUTEDinourBODIES?What does Vd means? Have you ever thought of how all the drugs that gets into our bodies distribute and what volume they contribute to? Probably no, well, let’s give a basic idea of what a drug volume of distribution (Vd) is. Its defined as the apparent volume that measure the ratio of the amount of drug dose in the body to the concentration of the drug in plasma (C)(1). It’s the volume that is needed (apparently) to maintain the total amount of the drugs to an equal concentration of plasma homogenously (1). Now, where are drugs distributed? Where do they go to kill your pain? A drug can be distributed in different areas of the body fluid. Figure 1 illustrates that the total body system consists of almost 60% of water which count for like 40 L of volume distributed mainly in intracellular fluid (ICF) which is inside the cells and extracellular fluid (ECF). ECF has two constitutes, a 3L fluid constitutes of blood (plasma) and interstitial fluid (IF) that surrounds cells (4).

What happens to drugs the moment they enter body fluid compartments? Some drugs might have high molecular weight or binds greatly to plasma proteins as it gets trapped in blood and can’t leave the capillaries so will have a lower volume of distribution (5)(6). Some are highly water soluble (hydrophilic), these doesn’t pass the IF area and add up to almost 14L Vd in a 70 kg person (5). Also, some drugs are hydrophobic and passes the intracellular fluid part and cross the cell membrane to the intracellular fluid, hence have a higher volume of distribution (ex, 42 L in a 70 kg person) (5)(6).

How is Vd calculated?

Now moving to calculation, we calculate the volume of distribution by taking the drug dose administered in the body and divide that by the concentration of that drug in the blood plasma as its

shown in the equation below:

as Q describes quantity of drug dose measured in g, Vd describes volume of distribution measured in liters and Cp is concentration of drugs in blood plasma measured in g/l (7). Assumptions are made when calculating the apparent volume of distribution, assuming

that the drug will be distributed equally and instantly throughout the fluid constitutes (8).

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Figure1:totalbodywaterhttp://www.medicoaid.com/qod-349-extracellular-intracellular-fluid-volumes/

𝑽𝒅 =𝑸𝑪𝒑= 𝒈

𝒈/𝒍= 𝑳

Examples are a must, right? Warfarin Vs Paracetamol are explained below:

Warfarin: (brand name: Coumadin) is a drug with a low volume of distribution, it’s one of the extensively used drugs in recent days for anticoagulant treatment to prevent thrombotic disorders (9). It has a relatively high percentage of bounding to plasma proteins (ex, albumin) leaving behind a very small unbound portion which makes it favorable for therapeutic treatments (9). Warfarin binds 99% of plasma proteins, this property makes it unable to leave the blood to the Interstitial fluid and to be distributed only in plasma volume in a high concentration hence have a low Vd of 3 L/40 L (total body water) (figure 1). Due to its high plasma protein bounding, warfarin has a high duration of action of 2-5 days so its stays longer in therapeutic window and hence it stays more in the blood (11).

Paracetamol, on the other hand, has a relatively high volume of distribution of 65L, it usually moves around all the body tissues with a low affinity to bind to plasma membrane (10%) (12). So it gets broken easily and gets distributed easily to body tissues (12). Paracetamol has one of the favorable properties, it’s a lipophilic substance which means it that it has high affinity to fatty tissues and a low affinity binding to plasma proteins unlike warfarin. It high volume of distribution makes contribute to its low duration of action of 4 hours since it doesn’t stay in blood for a long time and mostly distribute to body tissues (13). To conclude our blog, we can say that the volume of distribution is a significant tool in our everyday pharmacology, help us to understand how different drugs dose and binding or unbinding to plasma proteins can have an effect on blood plasma concentration by having an apparent volume estimated.

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let’s make it simple, put a red herring in a bath with drug in it and take a sample of the bathwater, you will see that the drug concentration will be higher on the sample because of the high drug bounding to the red herring. This ‘red herring effect’ simplify plasma protein binding. And so a low Vd is resulted due to the high Conc. in sample (10)

Now, imagine a drug is placed in a bathtub and gets bounded to a sponge, the drug Conc. in the water will be lower since it’s not equally distributed in the tub. Hence, should have a high Vd due to the lower Conc. this simplify that Vd value goes up due to the tissue protein binding (10)

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Reference list:

1. Davis, P., Cladis, F. and Motoyama, E. (2011). Smith's anesthesia for infants and children. 8th ed. St. Louis, Mo.: Mosby.

2. Greenblatt, D. (2014). Volume of distribution - Again. Clinical Pharmacology in Drug Development, 3(6), pp.419-420.

3. MedicoAid. (2018). Extracellular & Intracellular Fluid Volumes. [online] Available at:

http://www.medicoaid.com/qod-349-extracellular-intracellular-fluid-volumes/ [Accessed 3 May 2018].

4. Courses.lumenlearning.com. (2018). Body Fluids and Fluid Compartments | Anatomy and Physiology II. [online] Available at: https://courses.lumenlearning.com/suny-ap2/chapter/body-fluids-and-fluid-compartments-no-content/ [Accessed 10 May 2018].

5. NOORY, N. and profile, V. (2018). Volume of Distribution. [online] N-pharmacology.blogspot.com.au. Available at: http://n-pharmacology.blogspot.com.au/2013/06/vi.html [Accessed 10 May 2018].

6. Stepensky, D. (2011). The Øie–Tozer model of drug distribution and its suitability for drugs with different pharmacokinetic behavior. Expert Opinion on Drug Metabolism & Toxicology, 7(10), pp.1233-1243.

7. Sciencedirect.com. (2018). Drug Distribution - an overview | ScienceDirect Topics. [online] Available at: https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/drug-distribution [Accessed 4 May 2018].

8. Deranged Physiology. (2018). Volume of distribution. [online] Available at:

http://www.derangedphysiology.com/main/cicm-primary-exam/required-reading/pharmacokinetics/Chapter%202.0.2/volume-distribution [Accessed 2 May 2018].

9. Rosengren, A., Karlsson, B. and Nicholls, I. (2012). Monitoring the Distribution of Warfarin in Blood Plasma. ACS Medicinal Chemistry Letters, 3(8), pp.650-652.

10. Holford.fmhs.auckland.ac.nz. (2018). [online] Available at: http://holford.fmhs.auckland.ac.nz/docs/volume-of-distribution.pdf [Accessed 5 May 2018].

11. Accessdata.fda.gov. (2018). [online] Available at:

https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/009218s108lbl.pdf [Accessed 6 May 2018].

12. Prescott, L. (1980). Kinetics and metabolism of paracetamol and phenacetin. British

Journal of Clinical Pharmacology, 10(S2), pp.291S-298S

13. Beggs, S. (2008). Paediatric analgesia. Australian Prescriber, 31(3), pp.63-65.