Bioavailability

Defn
• The estimation of the bioavailability of a drug in a given dosage form
is direct evidence of the efficiency with which a dosage form performs
its intended function.
• It is defined as rate and amount of drug, which reaches the systemic
circulation following the administration of a dosage form.

• In other words, it is the fraction of an administered dose that actually

reaches the systemic circulation in contrast to that stated on the label.
• Drug product: A finished dosage form that contains the active drug ingredient
generally, but not necessarily, in association with in active ingredients.

• Pharmaceutical equivalents:
• Drug products that contain identical amounts of the same active drug ingredients,
i.e. the same salt or the ester of the same therapeutic moiety in identical dosage
form, but not necessarily containing the same active ingredients.
• Tetracycline
• Chlortetracycline
• Oxytetracycline
• Pharmaceutical alternatives:
• Drug products that contain an identical therapeutic moiety, or its
precursor, but not necessarily in the same amount or dosage form or
as the same salt or ester
• Chloramphenicol succinate, chloramphenicol palmitate
• Pharmaceutical substitution: The process of dispensing a
pharmaceutic alternative for the prescribed drug product.
• E.g. Ampicillin suspension is dispensed in place of tetracycline
phosphate.
• It requires physician’s approval.
• Generic name: The established, non-proprietory or common name of
the active drug in a drug product
• E.g. acetaminophen

• Generic substitution: The process of dispensing a different brand or

unbranded drug product in place of the prescribed drug product.
• The substituted drug product contains the same active ingredient or
therapeutic moiety as the same salt or ester in the same dosage form
but is made by a different manufacturer.
• Therapeutic alternatives:
• Drug products containing different active ingredients which are
indicated for the same therapeutic or clinical objectives.

• Therapeutic equivalents
• Drug products that contain the same therapeutically active drug and
give identical effects in- vivo.
• Drug products may be considered therapeutically equivalent if they
are:
• 1. Pharmaceutical equivalents
• 2. Bioequivalent
• 3. Manufactured in compliance with good manufacturing practices.
• Therapeutic substitution:
• The process of dispensing a therapeutic alternative in place of the
prescribed drug product.
• E.g. amoxicillin is dispensed for ampicillin.
• Bioequivalent drug product:
• Pharmaceutical equivalents whose rate and extent of absorption may
not show a significant difference when administered at the same
molar dose of the therapeutic moiety under similar experimental
conditions, either in single dose or in multiple doses.
• Bioequivalent requirements:
• Requirements imposed by the FDA for in-vitro and or in vivo testing of
specified drug products which must be satisfied as a condition of
marketing.
• The influence of route of administration on drug’s bioavailability is
generally in the following order
• Parenteral> Oral > Rectal >topical

• Within the parenteral route, IV injection of a drug results in 100%

bioavailability as the absorption process is bypassed.

• The amount of drug that reaches to the systemic circulation is called

as systemic bioavailability.
• The term bioavailable fraction (F) refers to the fraction of
administered dose that enters the systemic circulation.
Purpose of bioavailability studies
• Bioavailability studies are performed for both approved active drug
ingredients or therapeutic moieties not yet approved for marketing by
the FDA.
• New formulations of active drug ingredients or therapeutic moieties
must be approved prior to marketing by the FDA.
• The FDA in approving drug product for marketing must ensure that
the drug product is safe and effective for its labelled indications for
use.
• The drug product meet – standards of identity, strength, quality and
purity.
• For unmarketed drugs which do not have full NDA (new drug application)
approval by the FDA,
• In-vivo bioavailability studies must be performed on the drug formulation
proposed for marketing.

• Essential pharmacokinetic parameters including

• the rate and extent of systemic absorption,
• elimination half-life and
• rates of excretion and metabolism
• should be established after single and multiple dose administration.
• In- vivo bioavailability studies are performed also for new formulations
of active drug ingredients or therapeutic moieties which have full NDA
approval and are approved for marketing.

• Clinical studies are useful in determining the safety and efficacy of the
drug product.
• BA studies useful in defining the drug product in terms of its affect on
the pharmacokinetic drug.
• Bioequivalency study is useful in comparing the bioavailability of a drug
from various drug products.
• Once the drug products are demonstrated to be equivalent, then the
efficacy of these drug products is assumed to be similar.
TYPES OF BIOAVAILABILITY
• The area under the drug concentration time curve is useful as a
measure of the total amount of unaltered drug that reaches the
systemic circulation.
• The AUC is dependent on the total quantity of available drug, Fraction
dose, divided by elimination rate constant Ke
• And the apparent volume of distribution Vd
• F is the fraction of the dose absorbed, after IV administration F is
equal to unity since the entire dose is placed into the systemic
circulation instantaneously.
• The drug is considered to be completely available after IV
administration.
• After oral administration of the drug, F may vary from a value of F=0
(no drug absorption) to F=1 (complete drug absorption)
IV bolus
100

80
Concentration

Area under concentration

60 curve (AUC)

40

20

0
0 5 10 15 20 25 30
Time 20
Oral dosage form (product A)
100

80
Area under concentration
Concentration

60 curve (AUC)

40

20

0
0 5 10 15 20 25 30
Time 22
• Bioavailability is usually determined by comparing the rate and extent
of absorption of the drug from the formulation under evaluation , to
the data obtained following the administration of a reference
standard.

• If the reference standard is an IV dose, it is referred to as absolute

bioavailability.
• If the reference standard is any other dosage form (other than IV) it is
known as relative bioavailability.
Absolute bioavailability
• The absolute bioavailability of drug in a drug product may be
measured by comparing the respective AUCs after oral and IV
administration.
• This measurement may be performed as long as Vd and Ke are
independent of the route of administration.
• Absolute bioavailability using plasma data can be determined as
follows: = [AUC] po/dose po
---------------------------------------------
[AUC]IV/dose IV
Absolute bioavailability
100 For the same dose
(IV vs. Oral), the
80
bioavailability is given
by:
Concentration

60

AUCoral
40 F
AUCIV
20

0
0 5 10 15 20 25 30
Time 26
Absolute bioavailability
• Absolute bioavailability using urinary drug excretion data can be
determined by the following
• = [Du]po/dose po
-------------------------
[Du]IV/dose IV
Where Du is the total amount of drug excreted in the urine.
The Absolute bioavailability is equal to F, the fraction of the dose which
is bioavailable.
Absolute bioavailability
• For drugs given vascularly such as by IV bolus injection, F = 1 since all
the drug is completely bioavailable.
Relative (apparent) bioavailability
• The relative bioavailability is the systemic availability of a drug from
one drug product (A) compared to another drug product (B).
• Is the bioavailability of drug product as compared to a recognized
standard.

29
Oral dosage form (product A)
100

80
Area under concentration
Concentration

60 curve (AUC)

40

20

0
0 5 10 15 20 25 30
Time 30
Oral dosage form (product B)
100

80
Concentration

60 Area under concentration

curve (AUC)

40

20

0
0 5 10 15 20 25 30
Time 31
Relative bioavailability
100 the bioavailability is
given by:
80
Concentration

60

AUCoral ( A)
40 F
AUCoral ( B )
20

0
0 5 10 15 20 25 30
Time 32
Relative bioavailability
• Where the drug product B is the recognized reference standard. This
fraction may be multiplied by 100 to give percent relative
bioavailability.
Relative bioavailability
• Where different doses are administered, a correction for the size of
the dose is made, as in the following eq.

• Relative bioavailability = [AUC]A/doseA

-------------------------------------------------
[AUC]B/doseB
Relative bioavailability
• Urinary excretion data may also be used to measure relative bioavailability, as
long as the total amount of intact drug excreted in the urine is collected.
• The percent relative bioavailability using urinary excretion data can be
determined as follows:

=
[Du]A
--------------- x 100
[Du]B
Where Du is the total amount of drug excreted in the urine.
Plasma drug level time curve
Chemical instability:
• Some drugs, such as penicillin G, are unstable in the pH of the gastric
contents.
• Others, such as insulin, are destroyed in the GI tract by degradative
enzymes.
Nature of the drug formulation:
• Drug absorption may be altered by factors unrelated to the chemistry
of the drug.
• For example, particle size, salt form, crystal polymorphism, enteric
coatings and the presence of excipients (such as binders and
dispersing agents) can influence the ease of dissolution and,
therefore, alter the rate of absorption.
• 1.Physical state of drug:- *Liquids are better absorbed than solid medicaments. *Aq solution are
more quickly absorbed than oily solution. Soluble medicaments like insulin suspension is more
readily absorbed than insoluble protamine zinc insulin suspension.
• 2. Particle size :-Smaller particle size provides greater surface area of drug thus improving its
Absorption. Small particle size is useful in absorption of corticosteroids and antibiotics like
chloramphenicol, griseofulvin and oral anticoagulants.
• 3.Cocentration:- Higher conc of a drug is better absorbed from the gut by passive diffusion.
• 4.Dissolution rate.: The absortion of a drug takes place only when the drug is in solution form.
Solution >suspension>powder> capsules>Tablets.
• 5.Absorbing surface: Larger the surface area of absorbing surface, more will be the absorption. As
compare to GI mucosa and pulmonary endothelium ,skin is the poor absorbing surface.Absorption
of drug from mouth cavity is faster because absortion of drug from vascular membrane is rapid.
Also drugs can be better absorbed from small intestine than from stomach, due to large surface
area.
• 6.Functional integrity of GIT :-Absorption of drug from GIT Decresed
by incresing peristalsis activity . Thus anticholinergic drug reduces gut
motility and affect the absortion.
• 7. Lipid Solubility: If a drug is to be absorbed it has to pass through
cell membranes of the mucous coat of GIt and then into circulation
via the blood capillaries or lymph channels.
• As the cell membrane of GIT is lipid in nature, The rate and degree of
absorption drug which is to be pass through this is dependent on its
solubility.
• 9. Degree of ionization:- Some substances like ethanol are unionized
and others like Ach are highly ionized in the gut.
• Majority of drugs are either weak acids or weak bases and at
physiological PH-7.4 they exist partly in the unionized form and partly
in the ionized form.
• The absorption process is usually proportional to the lipid solubility of
the drug. The absorption of Unionized form is greater because it is
more lipid soluble than ionised form.
• 10. PH of drug: Acidic drug are rapidly absorbed from stomach
because in the acidic medium of stomach these remain in the
unionised form. e.g. Salicylates and Barbiturates.