Factors Affecting Pharmacokinetics

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FACTORS AFFECTING PHARMACOKINETICS

Pharmacon- drug, Kineticos- movement
It deals with the movement of drugs within the body.
It includes the process of absorption, distribution, metabolism also known as
biotransformation and elimination of drugs in the body.
ABSORPTION:
Movement of drug from site of administration into circulation.
PARAMETER:
Bioavailability.
FACTORS AFFECTING ABSORPTION:
A. PHARMACEUTICAL FACTORS:
1. Physiochemical properties of drugs.
i. Drug solubility and dissolution rate.
ii. Particle size and effective surface area.
iii. Polymorphism and amorphism
iv. Lipophilicity of the drug
v. Drug stability
i. DRUG STABILITY AND DISSOLUTION:
FOR HYDROPHOBIC DRUGS:
Dissolution is rate limited step e.g., Giresefulvin.
FOR HYDROPHOBIC DRUGS:
Permeation is rate limited step e.g., Neomycin
ii. PARTICLE SIZE AND EFFECTIVE SURFACE AREA OF DRUG:
Smaller the size of drug particle greater is its surface hence, more absorption e.g.,
Digoxin.
iii. POLYMORPHISM AND AMORPHISM;
POLYMORPHISM:
Compound that form crystals with different molecular arrangements are
polymorphs.
These polymorphs have different physical properties such as dissolution rate and
solubility. E.g., 70% of barbiturate exhibit polymorphism.
AMORPHISM:
They have greater aqueous solubility because the energy required to transfer a
molecule from crystal lattice is greater than that required for non-crystalline solid.
E.g., Amorphous form novobiocin is 10 times more soluble than crystalline form.
iv. PSEUDOPOLYMORPHISM (HYDRATES OR SOLVATES):
When the solvent molecules are incorporated with the crystal lattice of the solid
are called solvates.
Solvates that exist in different crystalline forms are called pseudomorphs.
When the solvent is water then solvent is known as hydrate. E.g., Anhydrous form
of ampicillin dissolves at a faster rate due to high aqueous solubility.
v. LIPOPHILICITY AND DRUG ABSORPTION;
For optimum absorption, a drug should have sufficient aqueous solubility to
dissolve in fluids at absorption site and lipid solubility high enough to facilitate
the partitioning of drug in the lipoidal bio membrane i.e. drug should have perfect
HLB for optimum bioavailability.
2. FORMULATION FACTORS:
i. DISINTEGRATION TIME:
Rapid disintegration is important to have a rapid absorption so lower
disintegration time is required.
ii. MANUFACTURING VARIABLES:
a. Method of granulation: Wet granulation yields a tablet that dissolve faster than
those made by other granulating methods.
b. Compression force: Higher compression force yields a tablet with greater
hardness and reduced wettability and hence have a long D.T.
c. Nature and type of dosage form:
d. Pharmaceutical ingredients/Excipients: More the number of excipients in

dosage form, more complex the medicine is and greater the potential for
absorption and bioavailability problems.
3. PHYSIOLOGICAL FACTORS:
i. AGE:
In adults altered gastric emptying, decreases intestinal surface area
decreases gastric blood flow and higher incidence of achlorhydria
cause impaired drug absorption.
ii. GASTRIC EMPTYING:
It is the passage of drug from stomach to small intestine. It is delayed
when co-administered with food.
iii. INTESTINAL TRANSIT TIME:
As, intestine is the major site of absorption of most of the drugs. Long
intestinal transit is desirable for the complete absorption of drugs.
iv. GASTROINTESTINAL PH:
A difference in PH is observed between gastric and colon fluid. The
PH of gastrointestinal fluids influence the drug absorption in several
ways:
 Dissolution
 Stability
v. DIISEASE STATE:
Infection, malabsorption and surgeries affect the absorption of drugs to
a greater extent. E.g., Achlorhydria (infection) and Gastrectomy
(surgery).
vi. PRESYSTEMIC METABOLISM:
The main reason for the decrease in bioavailability are decreased
absorption or first pass metabolism.
Enzymes that affect presystemic metabolism of drugs are:
 Gut wall enzyme
 Hepatic enzyme
 Bacterial enzyme
DISTRIBUTION
It is defined as pattern of scatter of specified amount of drugs in various locations of the
body.
PARAMETER:
Volume of distribution (vd)
FACTORS AFFECTING DISTRIBUTION

a. Physiochemical properties of the drug
b. Binding to plasma and tissue proteins
c. Blood flow
d. Special compartments and barriers
e. Disease states
a. PHYSIOCHEMICAL PROPERTIES OF THE DRUG

Drugs molecular weight (<500 to 600 Da) easily cross the capillary membrane to
penetrate the extra cellular fluids except in CNS because junction between the capillary
endothelia cells are not tight.
Passage of drugs from ECF into the cells depends on:
i. Molecular size
ii. Degree of ionization
iii. Lipophilicity
b. BINDING TO PLASMA AND TISSUE PROTEINS

The binding of drug with plasma protein is usually reversible (weak chemical bonds),
covalent binding of reactive drugs such as alkylating agents occurs rarely.
The binding of individual drugs ranges from very little (e.g. theophylline) to very high
(e.g. warfarin).
- Acidic drugs bind to plasma albumin whereas basic drugs bind to alpha acid
glycoprotein.
i. Acid drugs Penicillin
ii. Basic drug Quinine
- Binding to tissue protein:
Tissue binding of drugs is generally reversible or in some cases irreversible.
(Covalent chemical binding)
c. BLOOD FLOW:
The rule of blood flow to tissue capillaries varies widely which cause unequal
distribution of cardiac output.
d. SPECIAL COMPARTMENTS AND BARRIERS:
a. Blood brain barrier:
A blood brain barrier consists of epithelial cells that are bonded by tight
junction. More lipophilic drugs are more likely to cross the blood brain barrier.
b. Placental barrier:
The maternal and fetal blood vessels are separated by a layer of trophoblastic
cells that together constitutes the placental barrier. The characteristics of PB
are generally same to BBB.
c. Other barriers:
The prostrate testicles and globes of ice contain barriers that prevent drug
penetration to tissues.
Lipid soluble drugs can penetrate and reach these structures freely, whereas
water soluble drugs entry is prohibited.
e. DISEASE STATES:
Distributer characteristics of severed drugs are altered in disease states.
E.g. In meningitis and encephalitis penicillin-G gain access to the brain due to
increased permeability of BBB.
METABOLISM
Enzyme catalysed chemical transformation of drugs within living organism.
FACTORS AFFECTING METABOLISM

a. Chemical
b. Biological
c. Altered physiological
d. Temporal
a. CHEMICAL FACTORS:
i. Enzyme Induction:
It is a process in which a drug induces of enhances the expression of an enzyme.
E.g. Rifampicin, if taken by a female parent taking contraceptives causes
decreased therapeutic effect leading to pregnancy.
ii. Enzyme Inhibition:
It decreases the drug metabolizing capacity of enzymes. E.g. Sulfonamides
decreases the metabolism of phenytoin so its blood level becomes toxic.
b. BIOLOGICAL FACTORS:
i. Age:
In infant microsomal enzyme system is not fully developed. The rate of
metabolism of infants is very low. E.g. Chloramphenicol. It does not have great
efficiency in infant. Toxic effects in the form of grey baby syndrome might occur.
ii. Gender:
- Male:
Males have higher BMR and can metabolize drugs more efficiently. E.g.
Propanol.
- Female
Woman on oral contraceptives metabolize drugs on a smaller rate.
iii. Genetics:
Drugs behave differently in different individuals some variations.
iv. Race/Species:
Axioms, Orientals, Blacks and Whites might have different drug metabolizing
capacity. E.g. Eckimos metabolize drugs faster than Asians.
Laboratory animals can metabolize drugs faster than man. E.g. barbiturates.
v. Diet:
Low protein diet decreases and high protein content in diet increases the drug
metabolizing ability.
c. PHYSIOLOGICAL FACTORS:
i. Pregnancy:
During pregnancy, metabolism of certain drugs is decreased while that of others is
increased. E.g. Phenytoin.
ii. Hormonal Imbalance:
Higher levels of one hormone may inhibit the activity of certain enzymes while
including activity of other. E.g. Hypothyroidism increases div g metabolizing
ability of digoxin while hyperthyroidism decreases it.
iii. Disease States:
Liver diseases such as hepatic cirrhosis reduces the hepatic drug metabolizing
ability and thus increases the half lives of almost all drugs.
d. TEMPORAL FACTORS:
During early morning, enzyme activity is maximum whereas it is minimum in late
afternoons.
EXCRETION:
It is the excretion of drug metabolites outside the body.
Parameter:
Clearance and Half-life.
FACTORS AFFECTING RENAL EXCRETION:
1. Urine pH and pka.
2. Urine flow rate.
3. Physiochemical properties of drugs.
4. Distribution and binding characteristics of drugs.
5. Blood flow to the kidneys.
6. Biological factors.
7. Drug interactions.
8. Disease states.
1. PH AND PKA OF THE URINE:
Many drugs are either weak bases or acids and therefore the pH of the filtrate can
affect tubular reabsorption of many drugs.
2. PHYSIOCHEMICAL PROPERTIES OF DRUGS:
Drugs with molecular weight less than 300 are excreted in kidney.
Molecular weight from 300 to 500 Daltons are excreted through urine and bile both.
3. BINDING CHARACTERISTICS OF THE DRUGS:
Drugs that bound to plasma proteins act as macromolecules and cannot be filtered.
Only unbound drug appears in glomerular filtrate.
4. BIOLOGICAL FACTORS:
SEX: Renal excretion is 10% higher in males than in females.
AGE: In comparison to adults, the renal excretion in new born is 30 to 40% less.
5. BLOOD FLOW TO THE KIDNEY:
Increased blood flow enhances the elimination.
6. URINE FLOOW RATE:
Reabsorption of only those drugs is affected whose reabsorption is pH sensitive.
7. DRUG INTERACTION:
Renal clearance of any drug is affected by any drug interaction that results in
alteration of binding characteristics, renal blood flow, active secretion, urine pH and
forced diuresis.
8. DISEASE STATE:
Renal dysfunction: It greatly cause the elimination of the drug that are primarily
excreted by kidney.
Uraemia: It results in drug accumulation and increased toxicity.

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FACTORS AFFECTING PHARMACOKINETICS

d. Pharmaceutical ingredients/Excipients: More the number of excipients in

FACTORS AFFECTING DISTRIBUTION

a. PHYSIOCHEMICAL PROPERTIES OF THE DRUG

b. BINDING TO PLASMA AND TISSUE PROTEINS

FACTORS AFFECTING METABOLISM

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