Whenever a drug is given orally it has to go through certain pathway to reach systemic circulation.
E.g out of 100 mg drug given orally if 80 mg gets absorbed & 20 gets excreted. 80 mg of absorbed drug then reaches the liver through portal vein. Liver is highly saturated with enzymes so it doesn't allow the drug to pass freely through it without metabolizing certain amount of drug. . So if 30 mg of absorbed drug gets metabolized in the liver remaining 50 mg of drug reaches the systemic circulation in the unchanged form. But Bioavailability is never expressed in mg it is always expressed in fraction. So Bioavailability is basically the fraction of unchanged from of the drug that reaches the systemic circulation following administration by any route.
Whenever drug is given intravenously 100% drug reaches the systemic circulation in an unchanged form. So the Bioavailability of the drug given intravenously is 100%, while that of the drug given orally is < 100%
Bioavailability of a drug depends on the rate and extent of absorption.
Rate of drug administration is determined by: site of drug administration and drug formulation.
Extent (amount) of drug absorption is determined by: route of drug administration.
Factors affecting drug absorption and Bioavailability- There are various pharmaceutical and pharmacological factors that affect the drug absorption.
FIRST PASS METABOLISM:-
The drug given orally first pass through GI wall and then reaches the liver through portal system. The drug can also be metabolized in the gut wall CYP3A4 enzyme which is a substrate for P-gp {P-glycoprotein (P-gp) is an active transporter which pumps drug out of the gut wall cells back into the gut lumen against the concentration gradient.) Normally, drug enters the intestinal lumen by passive diffusion (i.e along the concentration gradient). But P-gp causes drug efflux or drug wastage (i.e against the concentration gradient); The amount of drug that disappears contribute first pass metabolism. But first pass metabolism occur in LIVER > INTESTINE.
Some amount of drug while passing through the liver gets metabolized in the liver for the first time before reaching the systemic circulation this known as first pass metabolism.
Bioequivalence- it as comparison of 2 different brand products of a same drug.
E.g. if Drug company X designs a new drug - (BRANDED DRUG) it gets patency for suppose 20 yrs. So that no other company can legally copy this drug. But once the patency expires any other company can legally copy this drug (GENERIC DRUG) but requires approval by FDA. and FDA asks for BIOEQUIVALENCE certificate (i.e it checks if the compound produced by other company is equivalent to that of BRANDED DRUG.) It has to prove that amount as well as rate of absorption is similar. No company can copy the drug 100% as it is. therefore the acceptable range is +/- 20-25%. The drug can be chemically, pharmaceutically, Therapeutically & clinically equivalent.
Thank you
3. BIOAVAILABILITY
• 100% absorption not possible due to certain
factors that affect drug absorption.
• Liver- highly saturated with enzymes so it
does not allow drug to pass freely without
metabolizing certain amount of drug.
4. • Bioavailability is never expressed in mg.
• It is always expressed as Fraction (F)
–Here, 100 mg drug was given orally
– 50 mg (unchanged form) reached systemic circulation
– Bioavailability =
𝟓𝟎
𝟏𝟎𝟎
= 0.5
• Thus, bioavailability is fraction of unchanged drug reaching the
systemic circulation following administration by any route.
BIOAVAILABILITY =
𝐐𝐔𝐀𝐍𝐓𝐈𝐓𝐘 𝐎𝐅 𝐃𝐑𝐔𝐆 𝐑𝐄𝐀𝐂𝐇𝐈𝐍𝐆 𝐒𝐘𝐒𝐓𝐄𝐌𝐈𝐂 𝐂𝐈𝐑𝐂𝐔𝐋𝐀𝐓𝐈𝐎𝐍
𝐐𝐔𝐀𝐍𝐓𝐈𝐓𝐘 𝐎𝐅 𝐃𝐑𝐔𝐆 𝐀𝐃𝐌𝐈𝐍𝐈𝐒𝐓𝐄𝐑𝐄𝐃
Where, 0 < F 1
5. DEFINITION:
• Bioavailability is defined as “the rate and the extent to which the
active concentration of the drug is available at the desired site of
action (or bloodstream)” [as per US Food and Drug Administration].
• BIOAVAILABILITY is an absolute term which requires measurement
of both the true rate and total amount (extent) of the drug that reaches
the systemic circulation from an administered dosage form.
• EQUIVALENCE is a relative term which means a comparison of 2
different brand products of the same drug with a set of established
standards.
6. • The rate of absorption is determined by:
i. The site of administration: Fastest to slowest
ii. The drug formulation: Decreasing order
Rate of Absorption:
Intravenous
(i.v)
Sublingual Rectal Oral
Solution Suspension Capsule Tablet
Coated
tablet
7. • For drug administered i.v- Bioavailability is 100 %
• For drugs administered i.m / s.c- Close to 100%
• But for drugs administered orally: Bioavailability is < 100%.
(due to lack of absorption from the gut).
Extent (amount) of absorption:
TOO HYDROPHILIC DRUGS
(Atenolol)
cannot cross lipid cell
membrane
TOO LIPOPHILIC DRUGS
(Acyclovir)
Cannot cross water layer
adjacent to the cell
8. • Both rate of absorption and extent of input can influence the clinical effectiveness
of a drug.
• Blood concentration-time curves, shows that the changes in the rate of absorption
and extent of bioavailability can influence both the duration of action and the
effectiveness of the same total dose of the drug administered in 3 different
formulations.
9. MEASUREMENT OF BIOAVAILABILITY:
% BIOAVAILABILITY (Fab) =
𝐀𝐑𝐄𝐀 𝐔𝐍𝐃𝐄𝐑 𝐓𝐇𝐄 𝐂𝐔𝐑𝐕𝐄 (AUCoral)
𝐀𝐑𝐄𝐀 𝐔𝐍𝐃𝐄𝐑 𝐓𝐇𝐄 𝐂𝐔𝐑𝐕𝐄 (AUC𝐢
.
𝐯
)
x 100
• To calculate bioavailability: drug is given by oral and i.v route to the same person.
• Compare the bioavailability of the active drug in systemic circulation following non-
invasive administration with the same drug following intravenous administration
10. a. Peak plasma concentration (Cmax)
b. Time to attain the peak plasma concentration (tmax)
c. The area under the curve (AUC) of plasma
concentration vs time curve (till plasma
concentration has fallen to 10% of the peak value.
simple indicators for
the rate of absorption.
AUC denotes the total amount of
drug absorbed into the circulation
during a specified period.
• From plasma concentration-time curves, thus obtained 3 imp characteristics are noted and
compared:
For the product to be
considered bioequivalent-
• Cmax , tmax & AUC should
be same
11. Methods to calculate AUC:
1. Planimeter: An instrument for mechanically measuring the area of
plane figures.
2. Cut and Weigh method: To cut out the area under curve on
rectilinear graph paper and weigh it on an analytical balance.
3. Mathematical: Using Trapezoid rule.
• Measurement of AUC is a better index of bioavailability for drugs to
be given for a longer period because here the total drug absorbed
becomes more crucial than the peak concentration achieved/ the time
required to achieve the peak concentration.
12. Factors influencing absorption and
bioavailability:
Pharmaceutical
Factors
Particle
Size
Salt Form
Crystal
Form
Water of
Hydration
Nature of
Excipients
and
Adjuvants
Degree of
Ionization
Pharmacological
Factors
Gastric
Emptying and
Gastrointestinal
motility
Gastrointestinal
Disease
Food and Other
Substances
First-Pass
Effect
Drug-Drug
Interactions
Pharmacogenetic
Factors
Miscellaneous
Factors.
13. Pharmaceutical Factors:
• On Oral Administration, 2 processes precede the actual absorption
process- i) Disintegration & ii) Dissolution
14. o Particle Size:
• Particle size
1
surface area
Dissolution rate surface area
Poorly soluble drugs
Microfined
(Microfined Aspirin)
Facilitate absorption
Anthelminthic drugs
Particle size is increased
Reduce its absorption
Particle size
has no consequence on
Freely water-soluble drugs.
No need to reduce the
particle size
e.g. PARACETAMOL
15. oCrystal Form:
• Absorption rate and bioavailability of a drug depends on its crystalline form.
Amorphous forms
Dissolves better than the crystalline forms,
As no energy is required to break the
crystalline lattice
Bioavailability- Increased
e.g. Amorphous chloramphenicol palmitate,
Amorphous novobiocin
16. oSalt Form:
• A dissolution rate of a particular salt is usually different from that of the parent
compound.
Salt form of
weakly acidic/
basic drugs
Improves the
solubility and
dissolution rate
Which
increases the
absorption
BETTER
BIOAVAILABILITY
THAN
Tolbutamide
&
Phenytoin
(Free drug)
E.g. Tolbutamide Sodium
&
Phenytoin Sodium
(Salt form)
17. oWater of Hydration:
• Many drugs can associate with water to produce crystalline forms called the
hydrates.
Anhydrous forms of
(Caffeine, theophylline and ampicillin)
Faster dissolution rate and
better bioavailability
(than hydrous form)
If water molecules are already
present in a crystal structure,
the tendency of the crystal to
attract additional water and
initiate dissolution process is
reduced, compared to
anhydrous form
19. o Nature of Excipients and Adjuvants:
e.g. PHENYTOIN TOXICITY-
In epileptic patients (1968)
where in DILANTIN SODIUM CAPSULE-
Calcium sulphate was replaced with Lactose.
• Nature of excipients have
tremendous effect on bioavailability
of Drugs like-
• Phenytoin, Digoxin, Levodopa,
warfarin, etc.
20. Pharmacological Factors:
o Gastric emptying and gastrointestinal motility:
• Factors that accelerate gastric emptying increases the bioavailability because, the
drug is exposed to larger surface area of small intestine early.
Gastric emptying is
promoted by
•Fasting
•Anxiety
•Gastrokinetic- Metoclopramide
Increases drug absorption
Gastric emptying is
retarded by
Fatty diet
Anticholinergic drugs
Decreases drug absorption
Increased peristaltic
activity
Diarrhea
Decreases drug absorption
21. oGastrointestinal disease:
• Pathological factors that affect drug absorption:
– In Coeliac disease (malabsorption of fats):
Amoxycillin and pivampicillin: show decreased absorption.
Cephalexin: show increased absorption.
Ampicillin: no change.
– In Crohn’s disease (chronic inflammation of ileum):
There is a disproportionate absorption of individual components from:
cotrimoxazole
Absorption of Trimethoprim: decreased.
while Sulfamethoxazole: increased.
– In Gastroenteritis: decreased absorption of drugs if given orally.
22. o Food and other substances:
• But both the rate and extent of absorption of certain antibiotics e.g.
Rifampicin: is reduced after meals.
• Absorption of Tetracycline: reduced if taken with milk or milk products.
(forms poorly absorbed complexes with the calcium ions).
• Vitamin C: keeps Iron in ferrous form and increases its bioavailability.
• Absorption of Anti-fungal drugs (Griseofulvin): enhanced by absorption of
drugs with Fatty diet.
Empty stomach
Favors g.i absorption
Ingestion of food
Reduces rate of
absorption (not extent)
23. o First-pass effect:
• All drugs taken orally, first pass through GIT wall and then through Portal system before
reaching systemic circulation.
• A drug can be metabolized in the gut wall (e.g. CYP3A4- enzyme system- substrate for P-gp) or
in the portal circulation before reaching the systemic circulation.
• LIVER > Intestine.
• Net result: decreased bioavailability and diminished therapeutic response.
• Bioavailability of L-dopa, morphine, nitroglycerin, isosorbide dinitrate and
propranolol/labetalol is less, if given orally- due to significant first-pass effect
25. o Pharmacogenetic factors:
• Large differences in bioavailability often exist among humans due to
pharmacogenetic reasons.
• Show Increased bioavailability
Slow acetylators of
Isoniazid
(American Whites)
• Show Reduced bioavailability
Fast acetylators of
Isoniazid
(Japanese, Chinese)
Isoniazid Induced
Neurotoxicity
26. oMiscellaneous factors:
• Route of administration:
Parenteral > Rectal > Oral >
Topical.
• Area of absorbing surface:
Drugs better absorbed from small
intestine than from the stomach because
of the larger surface area of the small
intestine.
• State of circulation at the site of absorption
(in shock- where tissue perfusion gets
decreased)
Larger surface
area
Better
absorbed
27. • When 2 drugs- Drug A and Drug B are said to be bioequivalent?
• E.g., Drug company X- designs a new drug (BRANDED DRUG)
Patent for suppose-20 years. (no other company can copy this drug)
once patency expires, now any other company can legally copy this drug
(GENERIC DRUG)
But, needs approval by FDA- (asks for bioequivalence certificate)
i.e., if compound produced by A,B… companies is equivalent to compound produced by X.
i.e., It has to prove that Amount as well as rate of is similar.
• Bioequivalence: 2 pharmaceutically equivalent compound with similar rate and extent of
absorption.
• Bioequivalence is required for approval of generic drug.
• Range: normal acceptable range- 20-25 %
Needs Research,
Investments, trials
costly
No investments cheap
BIOEQUIVALENCE
28. Definition:
• EQUIVALENCE is a relative term which means a comparison of two
different brand products of a same drug with a state of established
standards.
• If 2 or more similar dosage forms of the same drug reaches the blood
circulation at the same relative rate and extent, these are called
BIOEQUIVALENT preparation of the generic drugs.
• Difference in the bioavailability is usually seen with oral dosage forms,
because bioavailability of any drug given i.v- 100%. (i.m & s.c close to
100%).
• Difference of < 25% in bioavailability among several drug formulations of
one drug will usually have no significant effect on clinical outcome, hence
such formulations can be called BIOEQUIVALENT
29. Types of Equivalence:
Chemical Equivalence:
If two or more dosage forms of the same drug contain the same labeled quantities
of the drug as specified in pharmacopoeia, these are chemical equivalent drugs.
2 Brands of a drug
May be chemically equivalent
But may not be bioequivalent
31. Therapeutic Equivalence:
If 2 brand products of 1 drug provide an “identical in vivo pharmacological
response” as measured by control of symptoms or a disease and safety profile they
can be considered therapeutically Equivalent.
They may or may not be
Pharmacokinetically equivalent
32. Clinical Equivalence:
If one structurally different drug can provide the same clinical response as another
mechanically related drug, they exhibit clinical equivalence.
33. References:
• Goodman L.S, Goodman & Gilman’s Pharmacological Basics of
Therapeutics, 13th edition, New York; New Delhi, Tata McGraw-Hill
Education, 2017.
• Katzung B.G, Basic and Clinical Pharmacology, 14th edition, New
York; New Delhi, Tata McGraw-Hill Education, 2017.
• Tripathi K.D., Essentials of Medicine Pharmacology 8th edition, New
Delhi, Jaypee Brothers Publications, 2019.
• Sharma H.L, Principles of Pharmacology, 3rd edition, New Delhi,
Paras Medical Publisher, 2018.
