ADME

1. Department of Pharmacology

2. ABSORPTION

3. • Absorption is movement of the drug from its site of
administration into the circulation.
• Not only the fraction of the administered dose that gets absorbed,
but also the rate of absorption is important.
• Except when given i.v., the drug has to cross biological
membranes; absorption is governed by the above described
principles
• Most of drugs are absorbed by the way of passive transport

4. Factors affecting absorption
• Drug properties: Lipid solubility, molecular weight and polarity
• Blood flow to the absorption site
• Total surface area available for absorption
• Contact time at the absorption surface
• Affinity with special tissue

5. Aqueous solubility
• Drugs given in solid form must dissolve in the aqueous biophase
before they are absorbed.
• For poorly water soluble drugs (aspirin, griseofulvin) rate of
dissolution governs rate of absorption.
• Ketoconazole dissolves at low pH: gastric acid is needed for its
absorption.
• Obviously, a drug given as watery solution is absorbed faster than
when the same is given in solid form or as oily solution.
Concentration
• Passive diffusion dépends on concentration gradient; drug given
as concentrated solution is absorbed faster than from dilute
solution.

6. Area of absorbing surface
• Larger is the surface area, faster is the absorption.
Vascularity of the absorbing surface
• Blood circulation removes the drug from the site of absorption
and maintains the concentration gradient across the absorbing
surface.
• Increased blood flow hastens drug absorption just as wind
hastens drying of clothes.
Route of administration
• This affects drug absorption, because each route has its own
peculiarities.

7.  Route of administration
 Topical
• Depends on lipid solubility – only lipid soluble drugs are
penetrate intact skin – only few drugs are used
therapeutically
• Examples – GTN, Hyoscine, Fentanyl, Nicotine, testosterone
and estradiol
• Organophosphorous compounds – systemic toxicity
• Abraded skin: tannic acid – hepatic necrosis
• Cornea permeable to lipid soluble drugs
• Mucus membranes of mouth, rectum, vagina etc, are
permeable to lipophillic drugs

8.  Subcutaneous and Intramuscular
• Drugs directly reach the vicinity of capillaries – passes capillary
endothelium and reach circulation
• Passes through the large paracellular pores
• Faster and more predictable than oral absorption
• Exercise and heat – increase absorption
• Adrenaline – decrease absorption

9. Oral Route
 Physical properties – Physical state, lipid or water solubility
 Dosage forms
 Particle size
 Disintegration time and Dissolution Rate
 Formulation – Biopharmaceutics
 Physiological factors
 Ionization, pH effect
 Presence of Food
 Presence of Other agents
First pass metabolism
 Before the drug reaches the systemic circulation, the drug can be
metabolized in the liver or intestine.
 As a Result, the concentration of drug in the systemic circulation will
be reduced.

11. • Intravenous administration has no absorption phase
• According to the rate of absorption
• Inhalation → Sublingual → Rectal → intramuscular → subcutaneous →
oral→ transdermal
• Example – Nitroglycerine IV effect – immediate, Sublingual – 1 to 3 min
and per rectal – 40 to 60 min

12. Bioavailability
• Bioavailability refers to the rate and extent of absorption of a drug
from dosage form as determined by its concentration-time curve in
blood or by its excretion in urine.
• It is a measure of the fraction (F) of administered dose of a drug
that reaches the systemic circulation in the unchanged form.
• Bioavailability of drug injected i.v. is 100%, but is frequently lower
after oral ingestion, because:
 The drug may be incompletely absorbed
 The absorbed drug may undergo first pass metabolism in
intestinal wall and/or liver or be excreted in bile.
 Incomplete bioavailability after s.c. or i.m. injection is less
common, but may occur due to local binding of the drug

14. Bioavailability - AUC
Plasma
concentration
(mcg/ml)
0
5 Time
(h)
1
0
1
5
AUC p.o.
F = ------------ x 100%
AUC i.v.
AUC – area under the curve
F – bioavailability
MTC
MEC

15. Bioequivalence
• Oral formulations of a drug from different manufacturers or
different batches from the same manufacturer may have the same
amount of the drug (chemically equivalent) but may not yield the
same blood levels—biologically inequivalent.
• 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 under suitable test conditions.
• Before a drug administered orally in solid dosage form can be
absorbed, it must break into individual particles of the active drug
(disintegration).

16. • Differences in bioavailability are seen mostly with poorly soluble and
slowly absorbed drugs.
• Reduction in particle size increases the rate of absorption of aspirin
(microfine tablets).
• The amount of griseofulvin and spironolactone in the tablet can be
reduced to half if the drug particle is microfined.
• There is no need to reduce the particle size of freely water soluble
drugs, e.g.paracetamol.

18. DISTRIBUTION

19. • Reversible Transfer of a Drug between the Blood and the Extra
Vascular Fluids and Tissues of the body (Eg: fat, muscle and brain
tissue)
• Once a drug has gained access to the blood stream, it gets distributed to
other tissues that initially had no drug, concentration gradient being in
the direction of plasma to tissues.
• The extent and pattern of distribution of a drug depends on its
 Lipid solubility
 Ionization at physiological pH (a function of its pKa)
 Extent of binding to plasma and tissue proteins
 Presence of tissue-specific transporters
 Differences in regional blood flow.

20. • Movement of drug proceeds until an equilibrium is established
between unbound drug in the plasma and the tissue fluids.
• Subsequently, there is a parallel decline in both due to elimination.

23. Apparent volume of distribution (V)
• Presuming that the body behaves as a single homogeneous
compartment with volume (V) into which the drug gets
immediately and uniformly distributed
• “The volume that would accommodate all the drug in the body, if
the concentration throughout was the same as in plasma”

24. • Fluid volume that is required to contain the entire drug in the body at
the same concentration measured in the plasma.
• Calculated by dividing the dose that ultimately gets into the systemic
circulation by the plasma concentration at time zero (C0)
Vd= Amount of drug in body/Plasma concentration at time zero (C0)
• If 500 mg of drug reaches circulation…(total amount of drug ) and if
plasma concentration is 0.5 mg/ml. Vd will be 500/0.5 = 1000 ml.
• Which means you require 1000 ml of fluid to accommodate total 500
mg of drug at concentration of 0.5 mg/ml.
• At times it can be larger than total blood volume. (when drug has
been stored in peripheral tissues so lower blood concentration).
• At times it can be smaller than or equal to total blood volume (when
drug remains in vascular compartment)

25. Distribution into the water compartments of body

27. Plasma compartment
• Drugs having high molecular weight or extensively plasma protein
bound like heparin Vd= 4L
Extracellular fluid
• Low molecular weight but hydrophilic drugs – Aminoglycosides
Vd=14L
Total body water
• Low molecular weight and lipophilic, – E.g Ethanol Vd=42 L
Chloroquine– 13000 L
Digoxin – 420 L
Morphine – 250 L
Propranolol – 280 L
Streptomycin and
Gentamicin – 18 L

28. Plasma protein binding
• Most drugs posses physicochemical affinity for plasma proteins
 Acidic drugs bind to plasma albumin, basic drugs bind to
alpha-1--acid glycoprotein
 Reversible manner
 Extensive binding serves as a circulating drug reservoir
 Other proteins to which drugs can bind globulins,
transferrin, ceruloplasmin, tissue proteins &
nucleoproteins

30. Clinical implications of plasma protein binding
1. Highly plasma protein bound drugs does not cross membranes so
largely restricted to vascular compartments (smaller Vd).
2. Temporary storage of the drug which is not available for any
action.
3. High degree of protein binding generally makes the drug long
acting
4. Plasma concentrations of the drug refer to bound as well as free
drug.
5. One drug can bind to many sites on the albumin molecule.
Conversely, more than one drug can bind to the same site.

31. 6. Displacement reactions - (Drug interactions) – Salicylates displace
sulfonylureas & methotrexate. – Indomethacin, phenytoin displace
warfarin. – Sulfonamides and vit K displace bilirubin(kernicterus
in neonates).
7. In hypoalbuminemia, reduced binding leads to high concentrations
of free drug e.g. phenytoin and furosemide.
8. Other diseases: e.g. phenytoin and pethidine binding is reduced in
uraemia

32. Clinical implications of Volume of Distribution
• Dialysis is not very useful for drugs with high Vd e.g digoxin,
imipramine
• It helps in estimating the total amount of drug at any time
• Vd is important to determine the loading dose
Loading dose = Vd X desired concentration
Amount of drug = Vd X plasma conc of drug at certain time

34. Redistribution
• Highly lipid-soluble drugs get initially distributed to organs with
high blood flow (brain, heart, kidney) & later into bulky less
vascular tissues (muscle, fat)
• So plasma concentration falls and the drug is withdrawn from
these sites
• If the site of action of drug is one of highly perfused organs,
redistribution may result in termination of drug action.
• Greater the lipid solubility faster is the redistribution of drug.
• Anaesthetic action of thiopentone sod. injected i.v. is terminated in
few minutes due to redistribution.
• To overcome , give continuous infusion

36. Plasma Half Life

38. Blood Brain Barrier

39. Functions and Properties of the BBB
• Protects the brain from "foreign substances" in the blood that may
injure the brain.
• Protects the brain from hormones and neurotransmitters in the
rest of the body.
• Maintains a constant environment for the brain.
Properties of drugs that can cross BBB
• Low molecular weight
• High degree of lipid solubility
• Non ionized
• Tertiary structure and Free drug

40. Placental Barrier
• Lipoidal and allows free passage of lipophilic drugs
• P-Glycoprotein limits exposure to maternally administered drugs
• Also placenta is site of metabolism- lowers exposure to drugs
• Incomplete barrier
• Congenital anomalies

43. What is Biotransformation (Metabolism)?
• Chemical alteration of the drug in the body
• To convert non-polar lipid soluble compounds to polar lipid
insoluble compounds to avoid reabsorption in renal tubules
• Most hydrophilic drugs are less biotransformed and excreted
unchanged – streptomycin, neostigmine and pancuronium
• Biotransformation is required for protection of body from toxic
metabolites

44. Results of Biotransformation
1. Active drug and its metabolite to inactive metabolites – most
drugs (Ibuprofen, paracetamol, chlormphenicol)
2. Active drug to active product (phenacetin – acetminophen/
paracetamol, morphine to Morphine-6-glucoronide, digitoxin to
digoxin)
3. Inactive drug to active/enhanced activity (prodrug) – levodopa -
carbidopa, prednisone – prednisolone and enalapril – enalaprilat)
4. No toxic or less toxic drug to toxic metabolites (Isonizide to
Acetyl isoniazide)

45. • The primary site for drug metabolism is liver; others are—kidney,
intestine, lungs and plasma.
• Biotransformation of drugs may lead to the following
 Inactivation
 Active metabolite from an active drug
 Activation of inactive drug

46. 1. Nonsynthetic/Phase-I/
Functionalization reactions
A functional group is generated or exposed,
metabolite may be active or inactive.
2. Synthetic/Conjugation/ Phase II
reactions:
• An endogenous radical is conjugated to
the drug metabolite is mostly inactive;
except few drugs.
• e.g. glucuronide conjugate of morphine
and sulfate conjugate of minoxidil are
active.
Biotransformation - Classification

47.  Most important drug metabolizing reaction – addition of oxygen
or (–ve) charged radical or removal of hydrogen or (+ve) charged
radical.
 Various oxidation reactions are – oxygenation or hydroxylation of C-,
N- or S-atoms; N or O- dealkylation.
Examples – Barbiturates, phenothiazines, paracetamol and steroids.
 Involve – cytochrome P-450 monooxygenases (CYP), NADPH
(Nicotinamide Adenine Dinucleotide Phosphate) and oxygen
 More than 100 cytochrome P-450 isoenzymes are identified and
grouped into more than 20 families – 1, 2 and 3 … Sub-families are
identified as A, B, and C
Phase I - Oxidation

48.  In human - only 3 isoenzyme families important – CYP1, CYP2 and
CYP3
 CYP 3A4/5 carry out biotransformation of largest number (30–50%) of
drugs. In addition to liver, this isoforms are expressed in intestine
(responsible for first pass metabolism at this site) and kidney too
 Inhibition of CYP 3A4 by erythromycin, clarithromycin, ketoconzole,
itraconazole, verapamil, diltiazem and a constituent of grape fruit juice
is responsible for unwanted interaction with terfenadine and
astemizole, rifampicin, phenytoin, carbmazepine, phenobarbital are
inducers of the CYP 3A4

50. Nonmicrosomal Enzyme Oxidation
 Some Drugs are oxidized by non- microsomal enzymes (mitochondrial
and cytoplsmic) – Alcohol, Adrenaline, Mercaptopurine
 Alcohol – Dehydrogenase
 Adrenaline – MAO and COMT
 Mercaptopurine – Xanthine oxidase
Phase I – Reduction
 This reaction is conversed of oxidation and involves CYP 450 enzymes
working in the opposite direction.
 Examples - Chloramphenicol, levodopa, halothane and warfarin
Levodopa (DOPA)
Dopamine
DOPA-decarboxylase

51.  Cyclization: is formation of ring structure from a straight chain compound,
e.g. proguanil.
 Decyclization: is opening up of ring structure of the cyclic molecule
e.g. phenytoin, barbiturates
Phase I – Hydrolysis
 This is cleavage of drug molecule by taking up of a molecule of water.
 Similarly amides and polypeptides are hydrolyzed by amidase and
peptidases.
 Hydrolysis occurs in liver, intestines, plasma and other tissues.
Examples - Choline esters, procaine, lidocaine, pethidine, oxytocin

52. Phase II metabolism
 Conjugation of the drug or its phase I metabolite with an endogenous
substrate - polar highly ionized organic acid to be excreted in urine or
bile - high energy requirements
Glucoronide conjugation - most important synthetic reaction
 Compounds with hydroxyl or carboxylic acid group are easily
conjugated with glucoronic acid - derived from glucose
 Examples: Chloramphenicol, aspirin, morphine, metroniazole,
bilirubin, thyroxine
 Drug glucuronides, excreted in bile, can be hydrolyzed in the gut by
bacteria, producing beta-glucoronidase - liberated drug is
reabsorbed and undergoes the same fate - enterohepatic
recirculation (e.g. chloramphenicol, phenolphthalein, oral
contraceptives) and prolongs their action

53.  Acetylation: Compounds having amino or hydrazine residues are
conjugated with the help of acetyl CoA, e.g.sulfonamides, isoniazid
Genetic polymorphism (slow and fast acetylators)
 Sulfate conjugation: The phenolic compounds and steroids are
sulfated by sulfokinases, e.g. chloramphenicol, adrenal and sex steroids
 Methylation: The amines and phenols can be methylated. Methionine
and cysteine act as methyl donors. Examples: adrenaline, histamine,
nicotinic acid.
 Ribonucleoside/nucleotide synthesis: activation of many purine and
pyrimidine antimetabolites used in cancer chemotherapy.

54. Factors affecting biotransformation
 Concurrent use of drugs: Induction and inhibition
 Genetic polymorphism
 Pollutant exposure from environment or industry
 Pathological status
 Age

55. Enzyme Inhibition
• One drug can inhibit metabolism of other – if utilizes same enzyme
• However not common because different drugs are substrate of
different CYPs
• A drug may inhibit one isoenzyme while being substrate of other
isoenzyme – quinidine
• Some enzyme inhibitors – Omeprazole, metronidazole, isoniazide,
ciprofloxacin and sulfonamides

57. Enzyme Induction
 CYP3A – antiepileptic agents - Phenobarbitone, Rifampicin and
glucocorticoide
 CYP2E1 - isoniazid, acetone, chronic use of alcohol
 Other inducers – cigarette smoking, charcoal broiled meat, industrial
pollutants – CYP1A
 Consequences of Induction:
• Decreased intensity – Failure of Oral Contraceptive Pills
• Increased intensity – Paracetamol poisoning
• Tolerance – Carbmazepine
• Some endogenous substrates are metabolized faster –
steroids, bilirubin

60. Organs of Excretion
 Excretion is a transport procedure which the prototype drug (or
parent drug) or other metabolic products are excreted through
excretion organ or secretion organ
 Hydrophilic compounds can be easily excreted.
Routes of drug excretion
 Kidney
 Biliary excretion
 Sweat and saliva
 Milk
 Pulmonary

63. Hepatic Excretion
• Drugs can be excreted in bile, especially when the are conjugated with
– glucuronic Acid
• Drug is absorbed
• Glucuronidated or sulfatated in the liver and secreted through the bile
• Glucuronic acid/sulfate is cleaved off by bacteria in GI tract
• Drug is reabsorbed (steroid hormones, rifampicin, amoxycillin,
contraceptives)
• Anthraquinone, heavy metals – directly excreted in colon

65. Renal Excretion
 Glomerular Filtration
 Tubular Reabsorption
 Tubular Secretion

66. Glomerular Filtration
 Normal GFR – 120 ml/min
 Glomerular capillaries have pores larger than usual
 The kidney is responsible for excreting of all water soluble
substances
 All nonprotein bound drugs (lipid soluble or insoluble) presented to
the glomerulus are filtered
 Glomerular filtration of drugs depends on their plasma protein
binding and renal blood flow - Protein bound drugs are not filtered !
 Renal failure and aged persons

67. Tubular Reabsorption
 Back diffusion of Drugs (99%) – lipid soluble drugs Depends on pH of
urine, ionization etc.
 Lipid insoluble ionized drugs excreted as it is – aminoglycoside
(amikacin, gentamicin, tobramycin)
 Changes in urinary pH can change the excretion pattern of drugs
• Weak bases ionize more and are less reabsorbed in acidic urine.
• Weak acids ionized more and are less reabsorbed in alkaline urine
 Utilized clinically in salicylate and barbiturate poisoning – alkanized
urine (Drugs with pKa: 5 – 8)
 Acidified urine – atropine and morphine etc.

68. Tubular Secretion
 Energy dependent active transport – reduces the free concentration of
drugs – further, more drug dissociation from plasma binding – again
more secretion (protein binding is facilitatory for excretion for some
drugs)

70.  Bidirectional transport – Blood Vs tubular fluid
 Utilized clinically – penicillin Vs probenecid, probenecid Vs uric acid
(salicylate)
 Quinidine decreases renal and biliary clearance of digoxin by inhibiting
efflux carrier P-gp
 Acidic urine
 Alkaline drugs eliminated
 Acid drugs reabsorbed
 Alkaline urine
 Acid drugs eliminated
 Alkaline drugs absorbed

71. Kinetics of Elimination
 Clearance: The clearance (CL) of a drug is the volume of plasma from
which drug is completely removed in unit time
 Renal Clearance may be calculated from the plasma or blood
concentration (CP), the urinary concentration (CU) and the rate of flow of
urine (FU), by the equation.
 Clearance by a specific organ for ex., liver the clearance of a drug can be
calculated from

72.  First Order Kinetics (exponential): Rate of elimination is directly
proportional to drug concentration, CL remaining constant
 Constant fraction of drug is eliminated per unit time
 Zero Order kinetics (linear): The rate of elimination remains constant
irrespective of drug concentration
 CL decreases with increase in concentration
 Alcohol, theophyline, tolbutmide
Plasma half-life
• Defined as time taken for its plasma concentration to be reduced to half
of its original value – 2 phases rapid declining and slow declining
• t1/2 =In2/k
• In2 = natural logarithm of 2 (0.693)
• k = elimination rate constant = CL / V ; V = dose of IV/C
• t1/2 = 0.693 x V / CL

73. Target Level Strategy
 Low safety margin drugs (anticonvulsants, antidepressants, Lithium,
Theophylline etc. – maintained at certain concentration within
therapeutic range
 Drugs with short half-life (2-3 Hrs) – drugs are administered at
conventional intervals (6-12 Hrs) – fluctuations are therapeutically
acceptable
 Long acting drugs
 Loading dose: Single dose or repeated dose in quick
succession – to attain target conc. Quickly
 Maintenance dose: dose to be repeated at specific intervals
Loading dose = target Cp X V/F

74. Monitoring of Plasma concentration
 Useful in
 Narrow safety margin drugs – digoxin, anticonvulsants,
antiarrhythmics and aminoglycosides etc
 Large individual variation – lithium and antidepressants
 Renal failure cases
 Poisoning cases
 Not useful in
 Response mesurable drugs – antihypertensives, diuretics
 Drugs activated in body – levodopa
 Hit and run drugs – Reseprpine, MAO inhibitors
 Irreversible action drugs – Orgnophosphorous compounds

75. Prolongation of Drug action
 By prolonging absorption from the site of action – Oral and
parenteral
 By increasing plasma protein binding
 By retarding rate of metabolism
 By retarding renal excretion