Pharmacokinetics 101: Drug Distribution

After the drug get absorbed into systemic circulation , then it get distributed into different body fluid compartments (drug distribution)

Distribution of drugs into body fluid compartments

-Water distribution in human body: 60% of human body is water,
- for 80kg person water volume equals 42L, two thirds of it is within intracellular fluid which equals 28 L, and one third is extracellular which equals 14 L
- the extracellular fluid comprises the interstitial fluid volume and plasma volume, third of body water is extracellular fluid (14 L), 75% which is 10.5 L are in the interstitial space, 25% which is 3.5L are in plasma
-Some drugs distribute to the intravascular volume only, some others extend to intracellular and or extracellular and some distribute to everything
-For drugs administered IV route , it skips absorption and directly into distribution

•Blood flow to tissues: blood flow to tissues varies, blood flow to vessel rich organs (brain, liver and kidney) is greater than the skeletal muscle , adipose tissue and skin
•Capillary permeability: capillary structure varies in terms of the fraction of the basement membrane exposed by slit junctions between endothelial cells; e.g. in liver and spleen a significant portion of the basement membrane is exposed due to large discontinuous capillaries through which large plasma proteins can pass; in the brain on the other side, the capillary structure is continuous and there are no slit junctions (BBB)
•Cardiac output: drug distribution is slower if heart disease
•Degree of binding of the drug to plasma and tissue proteins
•lipophilicity of the drug: lipophilic drugs readily move across most biologic membranes, they dissolve in the lipid and penetrate the cell surface (because cell membrane is lipid) , hydrophilic drugs do not readily penetrate and need active transport or other form of transport

•Volume of distribution is the apparent volume of water into which the drug is distributed in the body after distribution equilibrium
•Volume of distribution is calculated by dividing the total amount of the drug reached the systemic circulation over the plasma conc. Of the drug after distribution equilibrium
•Drug distribute to plasma first (3.5L) then to interstitial space (10.5L) and finally to Intracellular space (28L)

-Volume of distribution for all drugs is available in resources and google
-Deciding the management of drug toxicity: if Vd< 5 L then you do dialysis to the patient because drug is confined to plasma , if Vd of drug > 41 L then dialysis is ineffective because drug is distributed to intracellular and tissue proteins , if between those numbers then dialysis might be or might not be effective
-Forensic medicine: You can identify the dose of the drug the person took by testing for the plasma concentration of that drug and by the vd=amount/plasma conc , you can find the amount
-Calculation of loading dose that is needed for the drug to be at effective concentration, by identifying the concentration needed in plasma and vd= amount / plasma, and you find the amount , by multiplying the vd by plasma conc : Ld = p conc * Vd
-Calculation of drug clearance: The vd Is important in equations like: T1/2 = 0.7*vd/ Clearance

•Most drugs when introduced into the body are bound to plasma proteins
•Reversible binding to plasma proteins sequesters drugs in no diffusible form and slows transfer out of the vascular compartment
•The drug that highly bound to plasma proteins have less distribution
•Albumin is the major drug binding proteins, and it may act as a drug reservoir
•As the concentration of free drug decreases due to elimination, the bound drug dissociates from albumin, this maintains the free drug concentration as a constant fraction of the total drug in the plasma

•biological effect of the drug related to the free part, the bound part is reservoir (not effective) -example if drug bound to proteins 99% and free 1% , only 1% is active , 99% is reservoir when the free part end , it release more free drug
•Binding of drug to plasma protein prolongs the duration of action of the drug
•if drug bind to plasma proteins in high conc like warfarin (99% bound, 1% active), any small displacement of the bound part by another drug (that also bind to plasma proteins) can lead to doubling of the free active part and lead to toxicity
•if patient have hypoalbuminemia (liver disease, nephrotic syndrome, pregnancy) , and you give them a drug that bind in high conc to plasma proteins, this might lead to toxicity , because the free part is going to be very high (dose adjustment needed)

•Many drugs accumulate in tissues leading to higher concentrations in tissues than in interstitial fluid and blood
•Drugs accumulate in tissues by binding to lipids, proteins or nucleic acids, drugs may also undergo active transport into tissues
•Tissue reservoirs may serve as a major source of the drug and prolong its actions or cause local drug toxicity
•Example: acrolein (metabolite of cyclophosphamide can cause hemorrhagic cystitis because it accumulates in the bladder)