Bioavailability of Drugs

Fraction of the dose of a drug contained in any dosage form that reaches the systemic circulation in
unchanged or active form administered through any route is known as bioavailability.

Drugs injected using intravenous route of administration have 100% bioavailability, while others have
much less bioavailability, because:
1. All of the drug may not be adsorbed

2. Metabolism of the drug might occur before reaching the site of action

Drugs not absorbed by the oral route are highly polar Drugs, thus have low bioavailability.
𝑜𝑟𝑎𝑙
𝐵𝑖𝑜𝑎𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = 𝐴𝑈𝐶 ∗ 100
𝐴𝑈𝐶 (𝐼/𝑉)

Where AUC is the area under the curve

X-axis represents time, while y-axis represents the plasma concentration.

Bioavailability is the ratio of the area calculated for oral route of administration to the intravenous route
of administration. It is determined by comparing the plasma levels of a drug after administration with
plasma drug level achieved by I/V injection.

Factors Affecting Bioavailability:

1. Route of administration
Drugs given by intravenous route have 100% bioavailability. Exception includes prostaglandins, which
are inactivated/metabolized in the lungs, therefore, their bioavailability may be zero after I/V injection.
Those given by intramuscular route have bioavailability less than I/V route but more than subcutaneous
route, while subcutaneous route has bioavailability more than the oral route. Only 10% of the dose of
digoxin reaches systemic circulation after oral administration because of lack of absorption and bacterial
metabolism within intestines. Even some of the Drugs given by oral route may have 100% bioavailability
but this is rare.
By rectal route, half of the drug undergoes first pass metabolism.

Chloramphenicol, an antibiotic, administered by intravenous route has bioavailability less than oral
route because it is present in pro form and has to be activated in the intestines.

Route Bioavailability Characteristics

Intravenous 100% Most rapid

Intramuscular 75≤100% Large volume may be injected but

painful method

Subcutaneous 75≤100% Smaller volume than IM, may be painful

Oral 5≤100% Convenient, first pass metabolism

occurs

Rectal 30<100% Less first pass metabolism than oral

route

Inhalation 5<100% Rapid onset

Transdermal 80≤100% Usually slow absorption, lack of first

pass metabolism and prolonged
duration of action

2. Factors affecting absorption

Factors affecting absorption may be classified as those related to the drug and those related to the
body. They have been discussed separately. If absorbance is decreased, bioavailability is decreased and
vice versa. For a drug to be readily absorbed, it must be hydrophobic yet have some solubility in
aqueous solution.

3. First pass metabolism

Pre systemic metabolism en-route from the route of administration to the site of action is known as the
first pass metabolism. Most common site of first pass metabolism is the liver because after absorption
the drug administered by oral route enters the portal circulation to reach the liver. First pass
metabolism may also occur in the intestines, lungs adrenals or any other organ.
Significance:
1. Drug undergoing first pass metabolism has low bioavailability, the dose must be adjusted
keeping this in mind.

2. If a person is undergoing a liver disease, bioavailability may be increased, because most

Drugsthen enter systemic circulation in unchanged form. The dose must be decreased otherwise toxic
effects might result.

Drugs undergoing first pass metabolism and sites:

a. Bronchial mucosa:
Prostaglandins, nicotine and isoprenaline

b. Intestinal mucosa:

Chlorpromazine, levo dopa, tyramine, alpha methyl dopa, testosterone and progesterone

c. Liver:

Glyceryltrinitrate, amitriptyaline, nortriptyaline, imipiramine, pentazocine, lignocaine, propanolol,

labetalol, cimetidine and pethidine.
Glyceryltrinitrate is administered sublingually, by oral route it has almost 0% bioavailability.

Lignocaine is a local anesthetic and antiarythmic drug, its bioavailability by oral route is also 0%.
Highly polar Drugs also have 0% bioavailability. They are not absorbed from the intestine. Examples
include streptomycin and gentamicin.

Extraction Ratio:

The effect of first pass metabolism on bioavailability is measured by extraction ratio.

𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝑏𝑦 𝑙𝑖𝑣𝑒𝑟
𝐸𝑥𝑡𝑟𝑎𝑐𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑖𝑜 =
𝐻𝑒𝑝𝑎𝑡𝑖𝑐 𝑏𝑙𝑜𝑜𝑑 𝑓𝑙𝑜𝑤
Where clearance is the amount of drug cleared from the unit plasma in unit time by liver.
𝑆𝑦𝑠𝑡𝑒𝑚𝑖𝑐 𝑏𝑖𝑜𝑎𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = 𝐴𝑏𝑠𝑜𝑟𝑝𝑡𝑖𝑜𝑛 x (1 − 𝐸𝑥𝑡𝑟𝑎𝑐𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑖𝑜)
4. Chemical Instability
Drug may be destroyed by the HCl or enzymes present in the GIT. Benzyl penicillin is not given orally
because it is destroyed by HCl. Parenteral route is generally preferred.

5. Quality control

Quality control is related mainly to different brands. One drug might be manufactured by different
companies. These brands have different bioavailability although the drug is same. The difference lies in
the manufacturing process.

a. Particle size:
Greater the size, smaller is the absorption. Size is inversely proportional to bioavailability. Small particle
size is important for absorption of corticosteroids, chloramphenicol and griseofulvin.
b. Diluents/Excipients

Inactive ingredients which do not have pharmacological action. These are important when the drug is
given in solid forms (tablets, capsules, pills). Drug before absorption must disintegrate and dissolute.
Disintegration and dissolution may differ with different brands. If dissolution time is more, bioavailability
will be less and vice versa.

These are added to:

• Increase bulk when dose is very low e.g. digoxin

• Adding stability, making drug resistant to environmental conditions

• Mask objectionable taste of drug

Excipients

Excipients are the inert substances added to the tablets or pills to increase their bulk because
sometimes the dosage is very small.

Diluents
Diluents are inert substances used in case of liquids. Commonly used diluents include lactate, lactose,
starch, sucrose, calcium phosphate.
Diluents and excipients may affect bioavailability of different brands. They may bind with the active
principle. Sometimes when the patient is taking one brand for a very long time, suddenly bioavailability
may change by changing the company.
c. Compression pressure

If tablets or pills are more tightly bound, the bioavailability is decreased.

d. Moisture content/Binding agents

Moisture content may act in two ways:

a. If the moisture content is more, disintegration time is less

b. Sometimes some Drugs when have more moisture, form lumps in the stomach, which decreases
their absorbance.

Thus moisture content may act both ways.

e. Polymorphism

When the drug is chemically same but different in arrangement of molecules, the phenomenon is
known as polymorphism. Arrangement of molecules may be different with different brands.

Disintegration time:
The time in which a solid dosage form administered orally releases the active drug for absorption is
called disintegration time.
Clinical Significance:
Bioavailability differs with the dosage forms. Drug in liquid form have more bioavailability than those of
solids, while gases have the highest bioavailability. This is why inhalation is used in bronchial asthma.

With the same brand, dosage form manufactured by different companies may differ in bioavailability.

Three terms are generally used:

a. Bioequivalent:
If two similar Drugs have the same bioavailability, they are called bioequivalent. If the two similar Drugs
do not have the same bioavailability, they are called non-bioequivalent.

b. Therapeutic equivalent

If two similar Drugsperform the same effect, have same efficacy and toxicity, then they are called
therapeutically equivalent.

c. Chemical Equivalent

If two Drugs are manufactured according to the same principles and criterion layed down in
pharmacopoeia (official book published by country to manufacture Drugsin that country), then they are
called chemically equivalent.

Two brands may be chemically equivalent but may not be bioequivalent and therapeutically equivalent
because they might differ in the factors mentioned above.

Sensitive Drugs :
1. Antimicrobials
2. Anticonvulsants

3. Corticosteroids
4. Cardio active Drugs

5. Oral antidiabetics

6. Chemotherapeutic agents for cancer

If patient is stabilized on one brand, it should not be changed, because if the bioavailability is decreased
the drug will have less effect or if the bioavailability is increased, it might lead to toxicity.

Antimicrobials:
Anti-tuberculosis Drugs have to be continued for six to nine months. Recurrence of disease might occur
on changing to brand with less bioavailability, although symptoms disappear after four weeks. Bacteria
may also become resistant.

Anticonvulsants:
Anticonvulsant dose is adjusted by starting from a lower dose to reach the state where patient is free
from fits. Drugs have to be continued for the whole life. If the brand is changed reappearance of
convulsions might occur due to decreased bioavailability. Phenytoin is a drug of low therapeutic index.
There exists small difference between toxic and therapeutic effects which must be taken care of.
Cardio active Drugs:

Cardio active Drugs like digoxin have low therapeutic index. Small changes in plasma levels may lead to
toxicity.

Oral antidiabetic Drugs:

Oral anti diabetic Drugs have to be continued for the whole life. If bioavailability is increased, it may lead
to hypoglycemia and fainting. Decreased bioavailability may cause hyperglycemia and diabetic
complications.
Chemotherapeutics have low therapeutic index too. Plasma levels of corticosteroids matter as well.

We have to adjust the dose so that therapeutic failure does not occur.

Therapeutic Index:

Therapeutic index represents the safety of a drug. Drugs having large therapeutic index and safer and
vice versa.

Where, LD50 is a dose which can kill 50% of the animals administered
ED50 is a dose which can save 50% of the animals
TD50 is the median toxic dose

ED50* is the median effective dose

Drugs having low therapeutic index include:

Anticonvulsants, lithium, anticoagulants, corticosteroids and cardio active Drugs.
Therapeutic Window:

Therapeutic window is the range between the high therapeutic index and low therapeutic index. Drugs
with low therapeutic index have a narrow therapeutic window.
Drugs having 100% bioavailability

Drugs having 100% bioavailability include chlordiazepoxide, diazepam, lithium, metronidazole,

phenobarbitol, salicylic acid, trimethoprin and valproic acid.