Bioavailability of drugs

1. Bioavailability
Dr.Muhammad Usman Khalid
DPT,MS-NMPT

2. Bioavailability
• It the fraction of drug that
reaches the systemic
circulation in a chemically
unchanged form, following
administration by any route

3. Bioavailability & route of administration
• I/V route = unity (one) or 100 %
By any other route may be less than 100 %
• I/M --- 75 to ≤100
• SC --- 75 to ≤ 100
• Oral --- 5 to ≤ 100
• Rectal --- 30 to ≤ 100
• Inhalation --- 5 to ≤ 100
• Transdermal --- 80 to ≤ 100

5. How bioavailability is measured
• It is measured by determining the
plasma drug concentration versus
time curves in a group of subjects
following oral and (on separate
occasion) I/V administration.

6. How bioavailability is measured
•Bioavailability =
AUCoral/AUCintravenous
– AUC --- area under the blood concentration curve

10. Factors affecting bioavailability
• Factors which reduce the bioavailability to < 100 %
• Reduced absorption from the site
of administration
•First pass elimination ---
Drug undergoes metabolism or
elimination prior to entering the
systemic circulation

11. Factors affecting the rate and extent of
absorption
•Nature of drug
formulation
•Chemical instability
•Solubility of the drug

12. Chemical instability
•Unstable in the pH of
gastric contents ---
penicillin G
•Destroyed in the GI tract by
enzymes --- insulin

13. Solubility of the drug
• Very hydrophilic drugs --- Poorly absorbed ---
unable to cross lipid rich cell membranes
• Extremely hydrophobic --- Poorly absorbed -
-- cannot gain access to the surface of the
cells
• Largely hydrophobic, yet have some
solubility in aqueous solutions --- Readily
absorbed

14. Pharmaceutical formulation and
bioavailability
• A drug is incompletely released from its
dosage form because of differences in
the pharmaceutical formulation
unrelated to the chemistry of the drug
• Particle size, salt form, enteric coating,
crystal polymorphism, compression
pressure during manufacturing,
moisture content

15. Pharmaceutical formulation and
bioavailability
• The special formulations may alter
absorption “slow release” or
“sustained-release” formulation
• “Enteric coating” prevents
breakdown of tablets by acid pH of
the stomach

16. “First-pass” effect
• “presystemic elimination” or
• “first pass elimination”
• The elimination in the intestine
and liver, which reduces the
amount of drug delivered to the
systemic circulation

17. Elimination in the intestine
• Excretion back into the intestinal lumen
• Metabolism

18. In the liver
• Metabolism
• Excretion into the bile

19. First pass hepatic metabolism
• If a drug is metabolized by the liver,
the amount of drug that reaches the
systemic circulation is decreased
• Significant biotransformation during a single
passage through the liver
• Propranolol and lidocaine

20. Extraction ratio
• The effect of first pass hepatic
elimination on bioavailability is
expressed as the extraction ration
CLliver
ER = --------------------
Q (hepatic blood flow)

21. Drugs with high extraction ratio
by the liver
• Propranolol
• Isoniazid
• Verapamil
• Morphine
• TCAs

22. Drugs that are poorly extracted
by the liver
• Warfarin
• Diazepam
• Phenytoin
• Theophyllin
• Toulbutamide and
• Chlorpropamide

23. Variation in Extraction ratio
•Marked variation in
bioavailability between
subjects because of
differences in hepatic
function and blood flow.

24. Alternative routes of administration
are used to avoid the first pass effect
• Parenteral routes --- Provides direct access to
systemic – not portal vein
• “Intra” ---Three common routes --- IV, IM, SC
• Topical --- To maximize concentration at
site of action and minimize it elsewhere
• Transdermal -- To prolong the duration of
drug absorption

25. Alternative routes of administration
are used to avoid the first pass effect
• By inhalation
• S/L absorption provides direct
access to systemic – not portal vein
• P/R
–Lower rectum --- into inferior vena
cava
–Upper rectum – to the liver

26. Significance of bioavailability
•Bioavailability
influence the clinical
effectiveness of a
drug

27. Bioavailability – and route of
administration
• Drugs that undergo near-complete
presystemic metabolism and thus
cannot be administered orally ---
nitroglycerine – given by sublingual
or transdermal route

28. Bioavailability – dose of the drugs
• Drugs with extensive presystemic metabolism
can still be administered by the oral route,
using much higher doses
• Verapamil – I/V – 1-5 mg, orally 40-120 mg
• Low dose aspirin --- result in exposure of
cyclooxygenase in platelets in portal vein to
the drug, but systemic sparing because of
first-pass aspirin deacylation in the liver

29. Bioequivalence / bioinequivalence
• For comparison of the bioavailability of the
“Generic equivalent of patented products”
• Different pharmaceutical
formulation of the same drug, are
given at same dose, by the same
mode and their bioavailability is
compared

30. Variation in oral absorption
among different formulation of digoxin

31. Bioequivalence
• When different pharmaceutical
preparations have same
bioavailability and the same rate of
absorption.
• When this occurs, the plasma levels
of the two products will be super
imposable

32. Bioinequivalence
• When different pharmaceutical
preparations are given and there is
significant difference in the
bioavailability & rate of absorption
• When this occurs, the plasma levels
of the two products will not be super
imposable

33. Therapeutic equivalence
• Two similar drugs are therapeutically
equivalent if they have comparable
efficacy and safety
• Clinical effectiveness
–Maximum serum drug concentration
–Time required (after administration) to
reach peak concentration

34. Bioequivalent VS Therapeutic
equivalence
•Two drugs that are
bioequivalent may not
be therapeutically
equivalent.

35. Bioavailability differences between
three preparations of a drug containing the same amount

36. Bioavailability differences between
three preparations of a drug containing the same amount
Bioavailability A = B (AAUC = BAUC)

37. Bioavailability differences between
three preparations of a drug containing the same amount
Bioavailability A = B (AAUC = BAUC)
B may not produce the therapeutic effect

38. Bioavailability differences between
three preparations of a drug containing the same amount
Bioavailability A = B (AAUC = BAUC)
B may not produce the therapeutic effect
C lower bioavailability

39. Rates of absorption
TimeEffect of rate of absorption on plasma concentration

40. THANK YOU