Drug Distribution
DRUG DISTRIBUTION
Distribution is the passage of drug molecules to liquid compartments and tissues in the body via transportation across the capillary membrane.
The body fluid compartments and volumes in which the drugs are distributed
The distribution of drugs can occur in 4 patterns throughout the body:
Ø Distribution only in plasma: HMW-Dextran, Evans blue dye, suramin
Ø Distribution to all body fluids homogenously: Small and non-ionized few molecules like alcohol, some sulfonamides.
Ø Concentration in specific tissues: iodine in the thyroid; chloroquine in the liver; tetracyclines in bones and teeth; high lipophilic drugs in fat tissue
Ø Non-homogenous (non-uniform) distribution pattern: Most of the drugs are distributed in this pattern according to their abilities to pass through the cell membranes or affinities to the different tissues
FACTORS AFFECTING THE DISTRIBUTION OF DRUGS
A) Diffusion Rate:
Ø There is a positive correlation between the diffusion rate of the drug and the distribution rate
B) The Affinity of the Drug to the Tissue Components:
Ø Some drugs tend to be concentrated in particular tissues.
C) Blood Flow (Perfusion Rate):
Ø There is a positive correlation between the blood flow in the tissue and the distribution of the drugs.
Ø Kidney, liver, brain, and heart have a high perfusion rate (ml/100 g tissue/min) in which the drugs distribute higher;
Ø Skin, resting skeletal muscle, and bone have a low perfusion rate.
Ø The total concentration of a drug increases faster in well-perfused organs.
D) Binding to Plasma Proteins:
Ø Drug that reaches the blood interact with plasma proteins and bind with them.
ØProtein-bound drugs do have not any therapeutic effects.
Ø It allows temporary drug storage, and reduces the elimination.
PROTEIN BINDING
Plasma Proteins:
ü Albumin
ü Alfa-1 Acid Glycoprotein (AAG/α-AGP)
ü Lipoproteins
ü Globulins
1. Albumin
Ø The most important protein (59% of total) that binds the drugs in blood is albumin for most of the drugs.
Ø Especially, the acidic drugs (salicylates, vitamin C, sulfonamides, barbiturates, penicillin, tetracyclines, warfarin, probenecid, etc.) are bound to albumin.
Ø It has 4 binding sites:
a. Warfarin site: NSAIDs, Sulfonamides, Phenytoin, Bilirubin.
b. Diazepam site: BDZs, fatty acid, Tryptophan, Probenecid, Penicillin.
c. Digitoxin site: digitalis alkaloid
d. Tomoxifen Site: tomoxifen
Ø If the two drugs have the same binding site, thus it can give rise to the displacement interaction and further cause drug accumulation, and toxicity.
2. Alfa Acid Glycoprotein
Ø Basic drugs (streptomycin, chloramphenicol, LA, TCAs, Prazosin, etc.) are bound to alpha-1 and alpha-2 acid glycoproteins.
3. Lipoproteins (chylomicron, LDL, HDL)
Ø Acidic- Diclofenac
Ø Neutral- Cyclosporin A
Ø Basic- Chlorpromazin
4. Globulins
a. α-1 (Transcortin)- Corticosteroids, thyroxine, cyanocobalamin
b. α-2 (Ceruloplasmin)- Vit A, D, E, K
c. β-1 (Transferrin)- Fe2+
d. β-2 – Caritinoids
e. γ-globulin- Antigens
**Some drugs like Phenytoin, Phenobarbital is bind with blood hemoglobin.
PROPERTIES OF PLASMA PROTEIN-DRUG BINDING
1) Saturable:
Ø One plasma protein can bind a limited number of the drug molecule
2) Non-selective:
Ø More than one kind of drug which has different chemical structures or pharmacological effects can be bound to the space on plasma protein
3) Reversible:
Ø The bonds between the drug and plasma protein are weak bonds like hydrogen or ionic bonds
Ø Bound fraction serves as “drug storage”. Only the free (unbound) fraction of the drug circulating in plasma can pass across the capillary membrane.
REDISTRIBUTION
Ø Some drugs (especially general anesthetics) which are very lipophilic, following the injection, firstly (initially) distributes to the well-perfused organs like central nervous system.
Ø Later, the distribution occurs to less perfused organs like muscles.
Ø At last, distribution of these drugs shifts to the very low-perfused tissues like adipose (fat) tissue.
Ø Redistribution results with the running away of the drugs from their target tissue and last their effect.
PASSAGE OF THE DRUGS TO CNS
Ø A blood-brain barrier exists (except in some areas in the brain) which limits the passage of substances.
Ø Non-ionized, highly lipophilic, small molecules can pass into the CNS and show their effects.
Ø Some antibiotics like penicillin can pass through the inflamed blood-brain barrier while it can’t pass through the healthy one.
PASSAGE OF THE DRUGS TO FETUS
Ø Placenta doesn’t form a limiting barrier for the drugs to pass to the fetus.
Ø The factors that play role in simple passive diffusion, affect the passage of drug molecules to the fetus.
ü Placental blood flow
ü Molecular size
ü Drug solubility in lipids
ü Fetal pH (ion trapping): fetal plasma pH: 7.0 to 7.2; pH of maternal plasma: 7.4, so according to the ion trapping rules, weak basic drugs tend to accumulate in fetal plasma compared to maternal plasma
VOLUME OF DISTRIBUTION
Volume of Distribution = Amount of drug administered (dose) (mg) / concentration of drug in plasma (mg/ml)
Vd (L)= X (mg) / PC (mg/L)
Ø Most of the time, the volume of distribution calculated in this way is not equal to the real total volume of physiological liquid compartments in which the drug is distributed. So it may be called as “apparent volume of distribution (Vd)”.
Ø Following a single-dose intravenous administration of a drug, a log plasma concentration-time graph is plotted according to the values of plasma concentration taken at particular time points.
Ø Then the formula is:
‘Volume of Distribution (Vd) = Dose (iv) / C0’
Ø Also, you can calculate the volume of distribution from the same graph by using AUC (area under the curve) and Ke (rate constant for elimination) like:
Volume of Distribution (Vd) = Dose (iv) / (AUC x Ke)
To know the volume of distribution (Vd) value of a drug helps us to calculate:
Ø The amount of drug found in the body at a particular time from the analyzed plasma drug concentration.
Ø The drug dose (loading dose) that has to be given (required) to obtain a desired plasma drug concentration.
Ø To find the rate constant for elimination from the formula:
Ke = Clearance / Vd
Ø Case: IV dose 10 mg, plasma vol. 2.5L and 7.5L tissue volume then calculate Vd, (Vd = X/PC)
ü At 0 time, PC0 = 10/2.5 = 4mg/L then Vd0 = 10/4 = 2.5L
ü At time t, PCt = 10/10 = 1mg/L then Vdt = 10/1 = 1
Ø High Vd (>20L) means Tissue Accumulation and causes toxicity (highly lipid soluble drugs).
Ø Low Vd (<10L) means drug drugs are present in intracellular fluid (blood).
KINETICS OF DISTRIBUTION
Ø One compartment model: In this model, the whole body is considered to be the compartment (the volume) in which the drugs and/or the metabolites are distributed homogenously.
Ø Two-compartment model: In this model, the whole body is divided into two compartments regarding the distribution of drugs.
