Lecture- 09
Chapter- 2: Introduction to Pharmacokinetics
Sabreena Chowdhury Raka
BPH- 224: Pharmacology- I
Senior Lecturer
Drug distribution
Distribution in pharmacology is a branch of pharmacokinetics which describes the reversible
transfer of drug from one location to another within the body.
Once a drug enters into systemic circulation by absorption or direct administration, it must be
distributed into interstitial and intracellular fluids. Each organ or tissue can receive different
doses of the drug and the drug can remain in the different organs or tissues for a varying amount of
time.
The distribution of a drug between tissues is dependent on
Vascular permeability
Regional blood flow
Cardiac output and perfusion rate of the tissue
Ability of the drug to bind with tissue and plasma proteins
Lipid solubility of the drug
Ionization at physiological pH
Presence of tissue specific transporter
The drug is easily distributed in highly perfused organs such as the liver, heart and kidney. It is
distributed in small quantities through less perfused tissues like muscle, fat and peripheral organs.
The drug can be moved from the plasma to the tissue until the equilibrium is established.
Apparent volume of distribution (V):
Presuming that the body behaves as a single homogenous compartment with volume V into which
drug gets immediately and uniformly distributed.
V = dose administered i.v / plasma concentration
E.g. suppose total drug in the body is 1000mg and plasma drug concentration is 50mg/L. So
apparent volume of distribution is 20L.
Plasma protein binding of drug:
It means the bonding between drug and plasma proteins usually by weak ionic bond. This
bonding takes place until the conc. of plasma protein and drug conc. is saturated. The rest drugs
remain in free form. The free form of drug produces actions, metabolized and excreted.
Drugs extensively bound to plasma proteins are largely restricted to the vascular compartment and
have low value. E.g. Diclofenac and warfarin (99% bound) ‘V’ = 0.15L.
Lipid insoluble drugs do not enter into cells. So ‘V’ approximates extracellular fluid volume.
E.g. Streptomycin (0.25L).
Drugs stored in other tissues may have ‘V’ much more than total body water or even body mass.
E.g. Propranolol (4L), digoxin (6L) because most of the drugs is present in other tissues and plasma
conc. is low.
Most drugs possess physicochemical affinity for plasma proteins.
Acidic drugs generally bind to plasma albumin (Barbiturates, Benzodiazepine)
Basic drugs bind to α1 acid glycoprotein (β-blocker, lidocaine)
Highly plasma protein binding drugs are largely restricted to the vascular
compartment because protein bound drugs do not cross membranes (except through large
paracellular spaces, such as in capillary). They have smaller volumes of distribution.
The bound fraction is not available for action. However, it is in equilibrium with the free
drug in plasma and dissociates when the concentration of free drug is reduced due to
elimination. Plasma protein binding acts as temporary storage of the drug. (Penicillin)
High degree of protein binding generally makes the drug long acting, because bound
fraction is not available for metabolism or excretion.
Redistribution:
Highly lipid soluble drugs get initially distributed to organs with high blood flow, i.e. brain,
kidney, heart etc. later, less vascular but more bulky tissues (muscle, fat) take the drug plasma
conc. falls and the drug is withdrawn from these site.
If the site of action of the drug is highly perfused organs, redistribution results in termination of
drug action.
E.g. Anaesthetic action of thiopentone sodium inj. is terminated in few minutes due to
redistribution.
Penetration into brain:
Blood brain barrier (BBB): Endothelial cells are closely adherent to each other. A basement is
present. A layer of astrocyte is present. This barrier is lipoidal and limit the entry of non-lipid drug.
E.g. streptomycin. Exception- levodopa.
Page 1 of 4
Passage into placenta:
Placental membranes are lipoidal and allow free passage of lipophilic drugs, while restricting
hydrophilic drugs. Placental efflux P-gp also serves to limit fetal exposure to maternally
administered drugs. However, restricted amounts of nonlipid soluble drugs, when present in high
concentration or for long period in maternal circulation, gain access to the fetus. Some influx
transporters also operate at the placenta. Thus it is incomplete barrier and almost any drug taken
by the mother can affect the fetus or the newborn (drug taken before delivery, e.g. morphine)
Page 2 of 4
