Pharmacokinetics; Absorption; Distribution

1. Pharmacokinetics –
Absorption & Distribution
Dr. Vikram Sharma
MBBS, MD Pharmacology (MAMC)
Senior Resident
Department of Pharmacology
ESIC Medical College & Hospital, Faridabad

2. Definition:
Pharmacokinetics is the quantitative study of drug
movement in, through and out of the body.

3. Absorption
Definition:
Absorption is the movement of drug from its
site of administration into the circulation.
Amount absorbed
Rate of absorption

4. Aqueous solubility
• Solid form  aqueous biophase (dissolution)
• Liquid vs Solid dosage forms
• Aspirin, Griseofulvin - dissolution governs absorption
Factors affecting Absorption

5. Concentration
• Passive transport depends on concentration gradient
• Concentrated solution is absorbed faster than dilute
Area of absorbing surface
• Larger it is, faster absorption
Vascularity of the absorbing surface
• Maintains conc gradient
• ↑ blood flow ↑ drug absorption
Route of administration
• Each route has its own peculiarities

6. Oral Route of administration &
Absorption
Effective barrier - epithelial lining of GIT (lipoidal)
Nonionized lipid-soluble drugs, e.g. ethanol readily
absorbed from stomach, intestine
Acidic drugs - mostly absorbed from stomach (why?)
Basic drugs - mostly absorbed from duodenum.
Abs from stomach slower- mucosa thick, covered with
mucus, surface area small.
In general, faster gastric emptying accelerates abs.
Particle size governs rate of dissolution, rate of abs.

7. Highly polar drugs e.g. Gentamicin, Neostigmine not
absorbed orally.
Certain drugs degraded in GIT, e.g. Penicillin G, Insulin
(Enteric coated tablets, Sustained Release preparations)
Efflux transporter P-glycoprotein (P-gp): extrudes drug
back into lumen. Digoxin, Cyclosporine
Oral Route of administration &
Absorption

9. Drug-food interaction –
• Dilutes drug, retards abs.
• Complexes with food constituents, e.g. Tetracyclines
with calcium present in milk.
• Food delays gastric emptying most drugs abs
better empty stomach.
(Exceptions  e.g. fatty food ↑ Lumefantrine abs.)
Oral Route of administration &
Absorption

10. Drug-drug interaction –
• Formation of insoluble complexes
E.g. Tetracyclines/ Iron - calcium salts/ antacids,
ciprofloxacin - sucralfate.
o Solution- two drugs at 2–3 hour intervals. (why?)
• Altered abs by gut wall effects:
o altering motility (anticholinergics, TCAs, metoclopramide) or
o causing mucosal damage (neomycin, methotrexate, vinblastine).
• Alteration of gut flora by antibiotics may disrupt
enterohepatic cycling (oral contraceptives, digoxin).
Oral Route of administration &
Absorption

11. Enterohepatic circulation
Refers to the process whereby a drug/ metabolite in the liver is secreted
into the bile, stored in the gall bladder, and subsequently released into the
small intestine, where the drug can be reabsorbed back into circulation
and subsequently returned to the liver.
Antibiotics ↓ bacteria in small intestine (which perform hydrolysis of estrogen metabolite found in bile
to free drug) metabolite excretedlower circulating conc. of ethinylestradiol.

12. • When giving drugs intravenously, the drug does not
have to cross biological membranes.
• Bioavailability is 100%.
Intravenous Route of
administration & Absorption

13. • Drug deposited directly in the vicinity of capillaries.
• Lipid-soluble drugs pass readily across capillary endo.
• Capillaries being highly porous do not obstruct
absorption of even large lipid insoluble molecules or
ions.  many drugs not abs orally are abs parenterally.
Subcutaneous & Intramuscular Routes
of administration & Absorption

14. Subcutaneous & Intramuscular Routes
of administration & Absorption
• Absorption from s.c. site is slower than i.m. site but both
faster, more consistent/ predictable than oral abs.
• Heat and muscular exercise ↑ drug absorption, while
vasoconstrictors e.g. Adrenaline injected with the drug
(local anaesthetic) retard absorption.

15. • Systemic absorption after topical ∝ lipid
solubility.
• Glyceryl Trinitrate, Fentanyl and Estradiol
• Organophosphate insecticides
• Rubbing the drug (in olegenous base)
• Occlusive dressing
• Abraded surfaces readily absorb drugs.
• Cornea is permeable to lipid soluble,
unionized Physostigmine but not to
highly ionized Neostigmine.
Topical Route of administration &
Absorption

16. Bioavailability
Definition:
Bioavailability refers to the rate and extent of
absorption of a drug from a dosage form
It is a measure of the fraction (F) of administered
dose of a drug that reaches the systemic circulation
in the unchanged/ intact form.
Absorption and First pass metabolism - two
important determinants of bioavailability.

17. Bioavailability can be calculated by comparing the
AUC (area under plasma concentration time curve)
for i.v. route and for that particular route.

19. I.V. = 100%
BA lower after oral ingestion as—
(a) Drug may be incompletely absorbed.
(b) Absorbed drug may undergo first
pass metabolism in intestinal wall/ liver
or be excreted in bile.
Incomplete bioavailability after s.c. or
i.m. less common, may occur due to
local binding.
Bioavailability (BA) of different routes

21. Bioequivalence
Concept & Definition:
• Two preparations of a drug are considered bioequivalent
when the rate and extent of bioavailability of the active
drug from them is not significantly different.
• Different manufacturers or different batches from the
same manufacturer
Two formulations of Same Drug (different companies)
but different excipients

22. Tablets/ capsules contain a number of other materials—
• Diluents
• Stabilizing agents
• Binders Excipients
• Lubricants
• manufacture process
Differences in bioavailability may arise due to variations
in disintegration and dissolution rates.

23. How to ensure if they give equal effects?

24. Bioequivalence
Many different pharmaceutical companies can
manufacture same compound (with same dose as well
as dosage form) e.g. Phenytoin available as Tab. Dilantin
as well as Tab. Eptoin.
If the difference in the bioavailability of these two
preparations (same drugs, same dose, same dosage
forms) is less than 20% - bioequivalent.
As the term implies, these are biologically equal i.e. will
produce similar plasma concentrations.

25. • Bioavailability variation assumes practical significance for
drugs with
 low safety margin (eg. Phenytoin, Digoxin) or
 dosage needs precise control (oral hypoglycaemics,
oral anticoagulants, antimicrobials).
Bioequivalence

27. Concept:
Once a drug has gained access to the bloodstream, it gets
distributed to other tissues that initially had no drug
(conc. gradient - plasma  tissues).
Distribution
Equilibrium: Unbound drug (plasma) ⇌ tissue fluids 
decline (elimination)

28. Apparent volume of distribution
(Vd)
Presuming that the body behaves as a single
homogeneous compartment
V = volume into which the drug gets immediately & uniformly distributed

29. Definition:
Hypothetical volume required to contain the administered
dose if that dose was evenly distributed at the
concentration measured in plasma.
Apparent volume of distribution
(Vd)

30. Just like absorption, distribution also depends
on some factors.

31. Lipid : water partition coefficient of the drug
• Drugs sequestrated in other tissues Vd maybe more than
total body water or even body mass.
• E.g. Digoxin 6 L/kg, Chlorpromazine 25 L/kg, Morphine
3.5 L/ kg
Factors affecting Vd

32. pKa value of the drug
• Lipid-insoluble (ionized) drugs do not enter cells.
• E.g. Streptomycin, Gentamicin 0.25 L/kg.
Factors affecting Vd

33. Degree of plasma protein binding
• Drugs extensively bound to plasma proteins are largely
restricted to the vascular compartment and have low
values
• E.g. Diclofenac and Warfarin (99% bound) V = 0.15 L/kg.
Factors affecting Vd

34. Plasma Protein Binding
• Acidic drugs → albumin
• Basic drugs → α1 acid glycoprotein
• Extent of binding depends on the individual compound:
Flurazepam 10%
Alprazolam 70%
Lorazepam 90%
Diazepam 99%

36. Clinically Significant Implications
(i) Highly PPB drugs largely restricted to the vascular
compartment, have lower Vd
(ii) Bound fraction not available for action.
Bound drug ⇌ Free drug
Bound fraction dissociates when Free drug↓ d/t
elimination.
Plasma Protein Binding (PPB)

37. Clinically Significant Implications
(iii) High PPB generally makes the drug long acting.
(iv) High PPB drugs are not removed by haemodialysis.
(v) Generally expressed plasma concentrations of the drug
refer to bound as well as free drug.
Plasma Protein Binding (PPB)

38. Clinically Significant Implications
(vi) “Displacement Interactions”
• The overall impact of many displacement
interactions is minimal
• Clinical significance is attained only in case of highly
bound drugs
• Two highly bound drugs do not necessarily displace
- Probenecid, Indomethacin
• Similarly, acidic drugs do not displace basic drugs
and vice versa. (why?)
Plasma Protein Binding (PPB)

39. “Displacement Interactions”
• Aspirin displaces Sulfonylureas.
• Aspirin displaces Methotrexate.
• Indomethacin, Phenytoin displace Warfarin.
• Sulfonamides, Vit K displace Bilirubin (kernicterus in
neonates).

40. (vii) Hypoalbuminaemia
(viii) Tissue storage
Drugs may also accumulate in specific organs or get
bound to specific tissue constituents.

42. Affinity for different tissues
• Tetracyclines (Bones, Teeth)
• Griseofulvin (Nails, Skin)
Fat : Lean body mass ratio
• Highly lipid soluble drugs (Thiopentone)
• Sluggish reservoir (less blood flow)
Factors affecting Vd

43. Pathological states
• Congestive heart failure
• Uraemia
• Cirrhosis of liver
• Altering distribution of body water, permeability of
membranes, binding proteins or by accumulation of
metabolites that displace the drug from binding sites.
Factors affecting Vd

44. Factors affecting Vd
1. Lipid : water partition coefficient of the drug
2. pKa value of the drug
3. Degree of plasma protein binding
4. Affinity for different tissues
5. Fat : lean body mass ratio
6. Diseases like CHF, Uraemia, Cirrhosis
7. Differences in regional blood flow

45. Redistribution
• Highly lipid-soluble drugs
• Highly vascular organs Brain, Heart, Kidney  Less vascular Muscle, Fat
• Plasma conc. falls, drug withdrawn  termination of action.
• Anaesthetic action of Thiopentone (i.v.) terminated in a few min.
• Relatively short (6-8 hr) hypnotic action of oral Diazepam/
Nitrazepam
Solution: Repeated/ continuous i.v. infusion over long
periods, the low perfusion sites get progressively filled up.

46. Penetration into brain and CSF
Limit the entry of nonlipid-soluble drugs, e.g. Gentamicin, Neostigmine, Dopamine
P-glycoprotein (P-gp)
Inflammation ↑ permeability

47. • Enzymatic BBB: MAO, cholinesterase, other
enzymes in capillary walls.
• BBB deficient at the CTZ in the medulla oblongata,
anterior hypothalamus. (Lipid insoluble drugs can cause vomiting)
Penetration into brain and CSF

48. Passage across placenta
• Free passage of lipophilic drugs, restricting hydrophilic
drugs.
• P-gp limits fetal exposure to maternally administered
drugs.
• Incomplete barrier - almost any drug taken by the
mother can affect the fetus (e.g. Morphine)

49. Thank You!
Thank you!

50. THANK YOU
ALL
vikramsharma161@gmail.com
8826012309
References:
• Pharmacological basis of therapeutics:;Goodman & Gilman; 13th edition
• Principles of Pharmacology; HL & KK Sharma; 3rd edition
• Essentials of Medical Pharmacology; K.D. Tripathi; 8th edition
;