Distribution of Drugs (D):

• It is the process by which drugs reversibly leave the bloodstream and enter the extravascular fluid and tissues.
• It is an important pharmacokinetic process as it determines the transport of drugs to their site of action and to the organs of metabolism and excretion.
• The extent to which a drug is distributed to a particular tissue or organ depends largely on its ability to penetrate the capillary endothelium and cross the cell membrane.

Factors Affecting Distribution of Drugs:

a. Physico-chemical properties of drug:

• Almost all drugs having molecular weight less than 500-600 Da easily cross the capillary membrane to penetrate into the extracellular fluids because of loose junction between capillary endothelium.
• Drug that is lipid soluble and unionized at blood and ECF pH penetrates the cell more rapidly than a polar and ionized drug.
• Only small water-soluble molecules and ions of size below 50 Da enter the cell through aqueous filled channels whereas larger size are restricted unless a specialized transport system exists for them.
• According to pH-partition hypothesis, basic drugs readily enter into acidic tissues and fluids including intracellular fluid and concentrate there.
• Similarly, acidic drugs attain high concentration on alkaline body fluids.

b. Binding to plasma and tissue proteins:

• Drugs are transported in the circulating blood in two forms; free form and bound to plasma protein.
• Free form of drugs are pharmacologically active drugs, diffusible and available for metabolism and excretion.
• Protein bound drugs are pharmacologically inactive, non-diffusible, and not available for metabolism or excretion as they cannot pass through capillaries and cell membrane.
• In circulating blood, there is a constant ratio between the bound and free fractions of the drug.
• When concentration of free-drug falls due to redistribution, metabolism or excretion, the free: bound ratio is maintained by dissociation of bound form.
• Thus, plasma protein binding mainly serves as reservoir which supplies free drug whenever required.
• Common blood proteins that bind to drugs are albumin, lipoprotein, glycoprotein and globulins.
• Acidic and neutral drug generally bind to albumin and basic drugs to α₁-acid glycoproteins.

Significance of plasma-protein binding:

• Plasma-protein bound drugs are non-diffusible. Therefore, high plasma protein binding reduces the efficiency of drug distribution.
• Plasma protein bound drugs are pharmacologically inactive. Therefore, heavy protein bound drugs are generally less efficacious and less potent.
• Protein bound drugs donot undergo metabolism and excretion through glomerular filtration. Therefore, heavily protein bound drugs generally have long plasma half-lives.
• Protein bound drugs may show drug-displacement interactions. Therefore, if a drug is heavily protein-bound, has narrow therapeutic index, and show small volume of distribution. Displacement may significantly increase the biological activity and possible toxicity of the drug.

Binding to tissue proteins:

• A drug may bind to one or more of the several tissue and gets accumulated there.
• A drug is said to be localized in tissue if its concentration in that tissue exceeds the concentration in plasma.
• Tissue-binding is important in distribution from two view points; Firstly, it increases the apparent volume of distribution, and secondly it results in the localization of the drug at a specific site in the body.
• Binding of drugs with tissues may be either reversible or irreversible.
• Irreversible binding usually occurs as a result of chemical activation of the drug, which then attaches strongly to the tissue protein by covalent chemical bonding.
• Reversible tissue binding is not harmful, but the strong reversible chemical binding often results in adverse effects and toxicity. For ex; irreversible covalent binding of paracetamol and chloroform metabolites with liver results in hepatotoxicity.

c. Blood flow and organ size:

• Drug distribution to a particular organ or tissue depends on the size of tissue and tissue perfusion rate.
• Highly perfused tissues such as lungs, kidneys, liver, heart, adrenals and brain are rapidly equilibrated with lipid-soluble drugs.
• Muscles and skin are moderately perfused, so they equilibrate slowly with the drug present in the blood.
• Adipose tissues, bones and teeth being poorly perfused take longer time to get distributed with the same drug.

d. Specialized compartments and barriers:

• There are certain compartments and barriers which are not accessible to drugs because of their anatomic make-up poses permeability restriction to drugs.
• Some of these compartments and barriers include blood-brain barrier, blood-CSF barrier and placental barrier.

Blood-brain barrier:

• It is a lipoidal barrier formed by the encirclation of capillary endothelial cells in the brain which lacks pores or gaps and have tight junctions.
• Since the blood brain barrier (BBB) is a lipoidal barrier, it allows only the drugs having high to moderate lipid solubility to diffuse passively.
• Ionized or polar drugs largely fail to enter the CNS. Some water soluble drugs and endogenous substances are transported to brain by carrier mediated transport system.
• There are certain sites in brain like chemoreceptor trigger zone (CTZ) and posterior lobe of the hypothalamus where BBB doesnot exist and at these sites brain may be exposed to some lipid insoluble and polar drugs also.

Blood-CSF barrier:

• It is formed mainly by the choroid plexus of lateral, third or fourth ventricles.
• Capillary endothelium that lines the choroid plexus have open junctions or gaps but the choroidal cells are joined to each other by tight junctions.
• For a drug to enter CSF from the blood, it can move within the open junctions between capillary endothelial cells but must pass through the tightly linked choroidal epithelial cells forming the blood-CSF barrier.
• Drug that enters CSF slowly fails to achieve high concentrations there because the bulk flow of CSF continuously removes the drugs. Therefore, for a drug, its concentration in brain is always higher than that in the CSF.

Placental barrier:

• The maternal and fetal blood vessels are separated by a layer of trophoblastic cells which together constitute the placental barrier.
• Lipid-soluble drugs pass freely into fetal circulation by diffusion and water-soluble drugs or essential nutrients cross the placental barrier by carrier-mediated process.
• Impermeability of placental barrier to polar compounds is relative than the absolute. So, care must be taken while administration of all types of drugs during pregnancy because of the uncertainty of their harmful effects on developing foetus.

e. Availability of specialized transport system:

• Some drugs are concentrated in some specific tissues as a result of their active uptake by specialized transport systems present in such tissues.
• For ex; iodine is actively concentrated into thyroid cells and guanethidine is distributed into the adrenergic nerve terminals.

f. Disease states:

• Distribution characteristics of several drugs are altered in disease states.
• In meningitis and encephalitis, blood-brain barrier becomes more permeable and polar antibiotics like Penicillin-G gain access to the brain.
• In hypoalbuminemia, plasma protein binding of drugs may be reduced and high concentration of free drugs may be attained.
• In CHF or shock, the perfusion rate to the entire body decreases that adversely affects distribution of drugs.

g. Physiological factor:

• In infants, BBB is poorly developed, myelin content is low and cerebral blood flow is more, all of which provide greater penetration of drugs in the brain.
• In obese animals, high adipose tissue can take up a large fraction of the lipophilic drugs through the perfusion rate of fats is low.
• During pregnancy, the growth of uterus, placenta, and fetus increases the volume available for distribution of drugs.

Foetus also represents a separate compartment in which drug can distribute