This presentation explains the basic concepts of bioavailability which is an important part of pharmacokinetic studies.

1. BIOAVAILABILITY
DR MRUNAL DHOLE
23-08-2016

2. LAYOUT
• Definition of Bioavailability
• History
• Types of Bioavailability
• Equivalence
• Measurement of bioavailability
• Bioequivalence and its significance
• Factors affecting oral bioavailability

3. BIOAVAILABILTY
• Bioavailability of a drug is defined as the fraction of drug or
percentage of drug that reaches systemic circulation in
unchanged form (fractional availability = F)
• According to the U.S. Food and Drug Administration (FDA),
bioavailability of a drug means the rate and extent to which
the active ingredient or active moiety is absorbed from a drug
product and becomes available at the site of action

4. PHENYTOIN TOXICITY
Sudden outbreak of phenytoin toxicity in Australia in 1968
Supply of inert excipient, calcium sulphate used in “Dilantin Sodium
Capsules” (100 mg) exhausted
↓
Replaced with lactose
↓
Faster dissolution
(lactose wetted easily)
↓
Quicker absorption
↓
Plasma concentration increased
(normally, 10-20 µg/ml)
↓
Toxicity
(posterior fossa tumor, ataxia of gait, double vision, vomiting)

5. VARIATIONS IN BIOAVAILABILITY OF
DIGOXIN
• In 1971, patients in a New York hospital were found to require
unusually large maintenance doses of digoxin
• A study was conducted with four healthy volunteers where
they were administered standard digoxin tablets from
different manufacturers
• Even though the digoxin content of the tablets was same,
there were gross differences in the plasma concentration
achieved
• This happened because of differences in particle size

7. TYPES OF BIOAVAILABILITY
1. ABSOLUTE BIOAVAILABILITY
• Bioavailability of an orally administered drug is compared with
the bioavailability obtained of the same drug when it is
administered intravenously
2. RELATIVE BIOAVAILABILITY
• Bioavailability of a formulation of a certain drug (A) is
compared with another formulation (B) of the same drug
• It is used to assess the bioequivalence of two drug products

8. EQUIVALENCE
• BIOEQUIVALENCE
Based on the plasma concentration achieved, if two or more
dosage forms of a drug achieve the same bioavailability they are
called bioequivalent.
• CHEMICAL EQUIVALENCE
Based on the chemical assay if two or more dosage forms of a
drug contain the same amount of drug, they are said to be
chemically equivalent
e.g. Crocin and Calpol tablets, both contain paracetamol (500
mg). Therefore, they can be considered as chemically equivalent.

9. • THERAPEUTIC EQUIVALENCE
If two different drugs produce the same therapeutic or clinical
response they are called therapeutically equivalent.
e.g. Imipramine, a tricyclic antidepressant and fluoxetine, a SSRI
produce the same effect for the treatment of endogenous
depression
• CLINICAL EQUIVALENCE
If the response produced by two or more brands of a generic
drug is same they are called clinically equivalent
e.g. The response produced by Calpol (paracetamol) and Crocin
(paracetamol) is same, so they are clinically equivalent

10. MEASUREMENT OF BIOAVAILABILITY
• After the drug is administered intravenously, its plasma
concentration is measured at different intervals
• On a separate occasion, the drug is given orally and similar
process is repeated
• A plasma concentration time curve is plotted for both i.v. and
oral concentration.
• The areas under these plasma concentration time curves is
measured.
• Bioavailability of the drug is calculated using the following
formula
F = AUC(oral) x 100/AUC(i.v.)
•

11. •AUC = Area under Curve
•Cmax = Peak plasma concentration
•Tmax = Time to attain peak plasma
concentration

12. MEASUREMENT OF AUC
• AUC is calculated using the Trapezoidal rule
• It consists in dividing the plasma concentration-time profile into
several trapezoids and calculating the AUC by adding the area of
these trapezoids
• It is expressed as mg x h/L

13. AREA UNDER CURVE
• Area under curve is dependent on the clearance of the
drug and the dose administered
For a drug that follows first order elimination,
• AUC is directly proportional to the dose
• AUC is inversely proportional to the clearance of the drug

14. BIOAVAILABILITY AND
BIOEQUIVALENCE
• For a generic formulation of a drug to be considered
bioequivalent to the patented one, the AUC, Cmax and
Tmax of both the formulations must be identical
• Differences of less than 25% in bioavailability among
different formulations of one drug will have no significant
effect on clinical outcome, hence they are accepted as
bioequivalent.

15. SIGNIFICANCE OF BIOEQUIVALENCE
Two different brands of the same drug need to be bioequivalent
when the drug
• obeys zero-order or mixed-order elimination kinetics
• has a narrow therapeutic index
If a patient is switched from one brand to another that are not
bioequivalent, two outcomes are possible:
• Therapeutic failure due to decreased bioavailability
OR
• Drug intoxication due to increased bioavailabilty

16. FACTORS AFFECTING ORAL
BIOAVAILABILITY
Pharmaceutical
1. Particle size
2. Drug as a salt
3. Drug as a crystal
4. Excipients and Adjuvants
5. Lipid solubility & degree
of ionisation
Pharmacological
1. Route of administration
2. Gastric emptying and gut
motility
3. Gastrointestinal disease
4. Food
5. Drug-Drug interactions
6. Pharmacogenetic factors
7. Splanchnic blood flow
8. Hepatic first pass
metabolism

17. DISINTEGRATION AND DISSOLUTION

18. PHARMACEUTICAL FACTORS

19. 1. PARTICLE SIZE
Decrease in particle size
↓
Increase in surface area
↓
Rapid dissolution of the drug
↓
Increased bioavailability
• Poorly soluble, slowly dissolving drugs are often marketed in
microfined form
e.g., Aspirin, spironolactone, griseofulvin, digoxin

20. 2. SALT FORM
Salts of weakly acidic drugs highly water soluble
↓
Free acidic drug from these salts precipitate in
microcrystalline form
↓
Faster dissolution rate
↓
Increased bioavailability
e.g. Tolbutamide sodium and phenytoin sodium have better
bioavailability than tolbutamide and phenytoin as free drugs.

21. 3. CRYSTAL FORM
• Sometimes the amorphous and anhydrous forms of drugs
have faster dissolution rate and thus have better
bioavailability than their crystalline form
E.g.,
1. Amorphous chloramphenicol palmitate
2. Anhydrous forms of caffeine, theophyliine and ampicillin

22. 4. EXCIPIENTS AND ADJUVANTS
Inert materials are added for various purposes.
• Filling materials to increase the amount of drug – starch,
calcium sulfate
• Binding agents – gum
• Wetting agents – lactose, polysorbate 80
Lactose and polysorbate 80 → increase solvent penetration and
reduce particle aggregation → faster dissolution → increased
absorption

23. 5. LIPID SOLUBILITY AND IONISATION
• The less ionized the drug is, the more is the lipid solubility →
better absorption
• Weakly acidic drugs are lipid soluble at acidic pH → absorbed
from stomach
e.g., aspirin
• Weakly basic drugs are lipid soluble at basic pH → absorbed
from ileum
e.g., pethidine
• Strong acids and bases are permanently ionized → not absorbed
on oral administration
e.g., heparin, succinylcholine
• Non-polar drugs are incapable of ionization → highly lipid
soluble → easily absorbed
e.g., prednisolone, digoxin, chloramphenicol

24. PHARMACOLOGICAL FACTORS

25. 1. ROUTE OF ADMINISTRATION
Route of administration Bioavailability (%) Characteristics
Intravenous (IV) 100 (by definition) Most rapid onset
Intramuscular (IM) 75 to ≤100 Large volumes, often
feasible; may be painful
Subcutaneous (SC) 75 to ≤100 Smaller volumes than IM;
may be painful
Oral (PO) 5 to <100 Most convenient; first pass
effects may be significant
Rectal (PR) 30 to <100 Less first pass effects than
PO
Inhalation 5 to <100 Often very rapid onset
Transdermal 80 to ≤100 Very slow absorption; used
for lack of first pass effect;
prolonged duration of
action

26. 2. GASTRIC EMPTYING AND GUT
MOTILITY
• Accelerated gastric emptying → Drug reaches the large
absorptive surface of small intestine sooner → Increased
absorption and thus increased bioavailability
• Stasis in diseases such as diabetic neuropathy, migraine and
use of anticholinergics → retarded gastric emptying →
Decreased absorption
• Metoclopromide stimulates gastric emptying → Increased
absorption of paracetamol in migraine
• Excessive peristaltic activity (as in case of diarrhoea) impairs
absorption

27. 3. GASTROINTESTINAL DISEASE
1. Gastroenteritis - decreased absorption of drugs in general
2. Pyloric stenosis → retards gastric emptying → reduced
absorption
3. Coeliac disease
• Amoxycillin, pivampicillin – impaired absorption
• Cephalexin – increased absorption
• Ampicillin – no change
4. Crohn’s disease
• Trimethoprim – decreased absorption
• Sulfamethoxazole – increased absorption

28. 4. FOOD
• Absorption is favoured by an empty stomach in case of
thyroxine and rifampicin
• Absorption of propranolol and lithium is increased after food
intake
• Absorption of griseofulvin is increased after intake of fatty
meal
• Vitamin C increases the absorption of iron by reducing it in
ferrous (Fe+) form
• Absorption of tetracyclines is markedly reduced if taken with
milk or milk products

29. 5. DRUG-DRUG INTERACTIONS
Drug-Drug interactions that decrease bioavailability
1. Liquid paraffin emulsifies fats → No absorption of fat soluble
vitamins (A,D,K and E)
2. Aluminium, calcium and magnesium
present in antacids bind with tetracyclines
Iron present in haematinics ↓
formation of a
chelated complex
↓
poorly absorbed
Drug-Drug interactions that increase bioavailability
• Probenecid → Blocks excretion of penicillin → Increased
bioavailability

30. 6. SPLANCHNIC BLOOD FLOW
• Increased after food consumption → Higher plasma
concentration of drugs, e.g. propranolol
• Decreased in hypovolaemia → reduces drug absorption, e.g.
heart failure

31. 7. PHARMACOGENETIC FACTORS
Acetylation of INH
• Can be slow or rapid
• Slow acetylation
↓
High bioavailability
↓
INH induced peripheral neuritis
(Israelis, Scandinavians)
• Rapid acetylation
↓
Increase in hepatotoxic
metabolites
↓
Low bioavailability
(Chinese, Japanese and 40% of
Indians, an autosomal recessive
trait)
Hydrolysation
of Succinylcholine
Presence of atypical plasma
pseudocholinesterase in some
individuals
↓
Succinylcholine hydrolysed very
slowly
↓
1/6th of the normal dose enough to
provide the same therapeutic effect

32. 8. FIRST PASS METABOLISM

33. HOW DOES FIRST PASS METABOLISM
AFFECT BIOAVAILABILITY?
Effect of first pass metabolism on bioavailability is expressed as
the extraction ratio (ER)
ER = CLliver / Q
where
Q = Hepatic blood flow (normally 90 L/hr in a person weighing 70
kgs)
Oral bioavailability of a drug can be determined from the
extraction ratio.
F = f x (1 – ER)
where
f = Extent of absorption

34. BIOAVAILABILITY OF MORPHINE
For morphine,
CLliver= 60 L/h/70 kg
Q = 90 L/h/70 kg
ER = CLliver / Q
Thus,
ERmorphine = 60/90 = 0.67
Since morphine is almost
completely absorbed
f = 1
F = f x (1 – ER)
Thus,
Fmorphine = (1- 0.67) = 0.33 =
33%

35. • Drugs with high extraction ratio (ER) have low oral
bioavailability
e.g. morphine, lidocaine, verapamil
• Increase in dose can help reach therapeutic plasma
concentrations by oral route of administration
• However there will also be an increase in the concentration of
drug metabolites compared to intravenous administration
↓
Toxicity
e.g. Lidocaine on oral administration causes central nervous
toxicity

36. ORAL BIOAVAILABILITY OF SOME
DRUGS
Oral Bioavailability Drugs
Negligible Heparin, gentamicin,
d-tubocurarine
15-20% Morphine, glyceryl trinitrate,
isoprenaline, pentazocine
50-70% Atenolol, nifedipine, digoxin,
propranolol
>90% Chloroquine, paracetamol,
phenytoin, warfarin, sodium
valproate
<=100% Diazepam, lithium,
indomethacin, tamsulosin

37. REFERENCES
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38. THANK YOU.