Pharmacokinetics is the study of how the body affects drugs. It involves absorption, distribution, metabolism, and excretion of drugs. Absorption is how drugs enter the bloodstream and distribution is how drugs spread to tissues. Metabolism converts drugs to inactive forms through phase I (oxidation) and phase II (conjugation) reactions. Excretion eliminates drugs from the body. Together, these processes determine the effects of drugs over time.

1. Pharmacokinetics
By;
Mrs. Kalaivani Sathish M. Pharm
Assistant Professor
PIMS - Panipat

2. What is Pharmacokinetics
how the human body act on the drugs?
 Pharmacokinetics is the quantitative study of drug
movement in, through and out of the body. Intensity of
effect is related to concentration of the drug at the site
of action, which depends on its pharmacokinetic
properties
 Pharmacokinetic properties of particular drug is
important to determine the route of administration,
dose, onset of action, peak action time, duration of
action and frequency of dosing

3. Relationship – Dynamics and Kinetics
Absorption
Distribution
Metabolism
Excretion
Dosage Regimen
Concentration in
Plasma
Concentration at the
site of action
Pharmacokinetics
Pharmacodynamics
Effect

4. The Pharmacokinetic Process

5. BIOLOGICAL MEMBRANE

6. Drug Transportation
Drug molecules can cross cell membrane by:
Passive Diffusion
Protein – mediated transport (carrier mediated)
Facilitated Transport
Active trnsport
 Primary
 Secondary

7. Passive transport
(down hill movement)
 Most important Mechanism for most of the Drugs
 Majority of drugs diffuses across the membrane in the direction of
concentration gradient
 No active role of the membrane
 The rate of the transport being Proportional to lipid : water partition
coefficient
 Lipid soluble drugs diffuse by dissolving in the lipoidal matrix of the
membrane
 A more lipid solid drug attains higher concentration in the membrane
and diffuses quickly.
 Also greater the difference in the concentration of the drug on the two
sides of the membrane, faster its diffusion.

8. Passive transport
Affecting factors :
the size of molecule
lipid solubility
polarity
degree of ionization
the PH of the environment
such as: fluid of body
fluid in cell
blood, urine

9. REMEMBER
The drugs which are Unionized, low polarity and
higher lipid solubility are easy to permeate
membrane.
The drugs which are ionized, high polarity and
lower lipid solubility are difficult to permeate
membrane.

10. pH Effect
Most of drugs are weak acids or weak
bases.
The ionization of drugs may markedly
reduce their ability to permeate
membranes.
The degree of ionization of drugs is
determined by the surrounding pH and
their pKa.

11. Henderson–Hasselbalch
Equation
pKa = negative logarithm of acid dissociation constant
[A-] = ionized Drug
[HA] = unionized drug

12. Implications
 Acidic drugs re absorbed are largely unionized in stomach and
absorbed faster while basic drugs are absorbed faster in intestines
 Ion trapping
 Acidic drugs are excreted faster in alkaline urine – urinary
alkalizers
 Basic drugs are excreted faster in acidic urine – urinary acidifiers

13. Filtration
 Passage of Drugs through aqueous pores in
membrane or through Para cellular space
 Lipid insoluble drugs can cross – if the molecular
size is small
 Majority of intestinal mucosa and RBCs have small
pores and drugs cannot cross
 But, capillaries have large paracellular space and
most drugs can filter through this

14. FILTRATION

15. Carrier Mediated Transport
 Involve specific membrane transport proteins know as drug
transporters or carriers – specific for the substrate
 Drug molecules bind to the transporter, translocated across
the membrane, and then released on the on other side of
the membrane.
 Specific, saturable and inhibitable
 Depending on Energy requirement - Can be either
Facilitated (passive) or Active Transport

16. Facilitative transporters
 Move substrate of a
single class (uniporters)
down a concentration
gradient
 No energy dependent
 Similar to entry of
glucose into muscle
(GLUT 4)

17. Active Transport – energy
dependent
 Active (concentrative) transporters
 can move solutes against a concentration gradient
 energy dependent
 Primary active transporters - generate energy
themselves (e.g. ATP hydrolysis)
 Secondary transporters - utilize energy stored in
voltage and ion gradients generated by a primary
active transporter (e.g. Na+/K+-ATPase)
 Symporters (Co-transporters)
 Antiporters (Exchangers)

18. Major Drug
Transporters• ATP-Binding Cassette Transporters (ABC) Super family –
Primary active transport
• P-glycoprotein (P-gp encoded by MDR1)
• Intestinal mucosa, renal tubules and blood brain barrier etc.
• Mediate only efflux of solute from cytoplasm - detoxification
 Solute Carrier (SLC) transporters – Secondary active transport
 Organic anion transporting polypeptides (OATPs)
 Organic cation transporters (OCTs)
Expressed in liver and renal tubules – metabolism and excretion of
drugs

19.  It involves the invagination of a part of the cell
membrane and trapping within the cell of a small
vesicle containing extra cellular constituents. The
vesicle contents can than be released within the cell,
or extruded from the other side of the cell.
Pinocytosis is important for the transport of some
macromolecules (e.g. insulin through BBB).
Pinocytosis

20. 1. Absorption of Drugs
 Absorption is the transfer
of a drug from its site of
administration to the blood
stream
 Most of drugs are
absorbed by the way of
passive transport
 Intravenous
administration has no
absorption
 Fraction of administered
dose and rate of absorption
are important

21. Factors affecting absorption
Drug properties:
lipid solubility, molecular weight, and polarity etc
Blood flow to the absorption site
Total surface area available for absorption
Contact time at the absorption surface
Affinity with special tissue
Routes of Administration (important):

22. Route of administration:
 Topical:
 Depends on lipid solubility – only lipid soluble drugs are
penetrate intact skin – only few drugs are used
therapeutically
 Examples – Hyoscine, Fentanyl, Nicotine, testosterone and
estradiol
 Organophosphorous compounds – systemic toxicity
 Abraded skin (burnt skin ): tannic acid – hepatic necrosis
 Cornea permeable to lipid soluble drugs (absorbed from
nasolacrimal duct) e.g. timolol may produce bradycardia
and pricipitate asthma.
 Mucus membranes of mouth, rectum, vagina etc, are
permeable to lipophillic drugs

23. Route of administration:
Subcutaneous and Intramuscular:
Drugs directly reach the vicinity of capillaries –
passes capillary endothelium and reach
circulation.
Capillaries having large paracellular spaces do
not abstract absorption of large lipid insoluble
molecules or ions.
Very large molecules are absorbed through
lymphatics.
Passes through the large paracellular pores
Faster and more predictable than oral absorption

24. Route of administration: 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

25. Oral Administration – 1st
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.

26. Absorption – contd.
Intravenous administration has no absorption phase
According to the rate of absorption:
Inhalation→Sublingual→Rectal→intramuscular→sub
cutaneous→oral→transdermal
 Example – Nitroglycerine:
 IV effect – immediate, SL – 1 to 3 min and per rectal
– 40 to 60 minute

27. 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.
 Practical Significance – low safety margin drugs

28. Biovailability – contd.
MTC
MEC

29. BIOEQUVALENCE
 Oral formulation of a drug from different manufactures
or different batches from the same mfr may have the
same amount of the drug (chemically equvalent) but
may not yield the same blood levels- biologically
inequivalent .
 Before a drug administered orally in solid dosage form
can be absorbed,it must break into individual particle of
the active drug (disintegration) .Tablets and capsules
contains-diluents,stabilizing agents ,binders ,lubricants
etc.

30. Manufacture process – force used in compressing the
tablet may affect disintegration.
The rate of dissolution – solubility, particle size, crystal
form,and other physical properties of the drug.
Differences in bioavilability- may arise due to variation in
Disintegration and dissolution rates.
Reduction in particle size↑es the rate of absorption of
asprin(micrifine tablet)

31. 2. Distribution of Drugs
 It is the passage of drug from the circulation to the
tissue and site of its action.
 The extent of distribution of drug depends on its
lipid solubility, ionization at physiological pH
(dependent on pKa), extent of binding to plasma and
tissue proteins and differences in regional blood
flow,
 Movement of drug - until equilibration between
unbound drug in plasma and tissue fluids

32. Volume of Distribution (V)
 Definition: Apparent Volume of distribution is defined as
the volume that would accommodate all the drugs in the
body, if the concentration was the same as in plasma
 Expressed as: in Liters
V =
Dose administered IV
Plasma concentration

33. Volume of Distribution (V)
Total Body Fluid = 42 L (approx.)

34. Volume of Distribution (V)
Chloroquin – 13000 liters, Digoxin – 420 L,
Morphine – 250 L and Propranolol – 280 L
Streptomycin and Gentamicin – 18 L

35. Factors influencing Vd
Lipid solubility (lipid : water partition
coefficient)
pKa of the drug
Affinity for different tissues
Blood flow – Brain Vs Fat
Disease states
Plasma protein Binding

36. Redistribution
Highly lipid soluble drugs – distribute to
brain, heart and kidney etc. immediately
followed by muscle and Fats

37.  later ,less vascular but more bulky tissues take up the
drug –plasma concentration falls and the drug is
withdrawn from the sites.
 Redistribution results in termination of the drug action.
 Greater lipid solubility of a drug ,faster is its
redistribution.
 Aneathetic action of thiopentone terminated in few min
due to redistribution.

38. Blood brain barrier (BBB): includes the capillary endothelial cells
(which have tight junctions and lack large intracellular pores) and an
investment of glial tissue, over the capillaries.
Brain and CSF Penetration

39. Brain and CSF Penetration –
contd
 BBB is lipoidal and limits the entry of non-lipid soluble drugs
(amikacin, gentamicin, neostigmine etc.).
(Only lipid soluble unionized drugs penetrate and have action on
the CNS)
 Efflux carriers like P-gp (glycoprotein) present in brain
capillary endothelial cell (also in intestinal mucosal, renal
tubular, hepatic canicular, placental and testicular cells)
extrude drugs that enter brain by other processes
 brain increases permeability of BBB)
 Dopamine (DA) does not enter brain, but its precursor
levodopa does. This is used latter in parkinsonism.

40. Placental Transfer
Only lipid soluble Drugs can penetrate –
limitation of hydrophillic drugs
Placental P-gp serves as limiting factor
But, REMEMBER, its an incomplete barrier –
some influx transporters operate
Thalidomide

41. Plasma Protein Binding
 Plasma protein binding (PPB): Most drugs possess
physicochemical affinity for plasma proteins. Acidic drugs
bind to plasma albumin and basic drugs to α1-glycoprotein
 Extent of binding depends on the individual compound.
Increasing concentration of drug can progressively saturate
the binding sites
The clinical significant implications of PPB are:
a) Highly PPB drugs are largely restricted to the vascular
compartment and tend to have lower Vd.
b) The PPB fraction is not available for action.
c) There is an equilibration between PPB fraction of drug and
free molecules of drug.

42. Plasma Protein Binding – contd.
d) The drugs with high physicochemical affinity for plasma
proteins (e.g. aspirin, sulfonamides, chloramphenicol) can
replace the other drugs(e.g. acenocoumarol, warfarin) or
endogenous compounds (bilirubin) with lower affinity.
e) High degree of protein binding makes the drug long acting,
because bound fraction is not available for metabolism,
unless it is actively excreted by liver or kidney tubules.
f) Generally expressed plasma concentrations of the drug refer
to bound as well as free drug.
g) In hypoalbuminemia, binding may be reduced and high
concentration of free drug may be attained (e.g. phenytoin).

43. 3. Biotransformation
Metabolism of Drugs

44. What is Biotransformation?
Chemical alteration of the drug in the body
Aim: 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 etc.
Biotransformation is required for protection of
body from toxic metabolites

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

46. Biotransformation - Classification
 2 (two) Phases of
Biotransformation:
• Phase I or Non-synthetic
– metabolite may be
active or inactive
• Phase II or Synthetic –
metabolites are inactive
(Morphine – M-6
glucoronide is exception)

47. Phase I - Oxidation
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 0-
dealkylation
Examples – Barbiturates, phenothiazines,
paracetamol and steroids

48. Phase I - Oxidation
 Involve – cytochrome P-450 monooxygenases (CYP),
NADPH 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 etc.
 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

49. 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(catechol –o-methyl
transferase)
Mercaptopurine – Xanthine oxidase

51. 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

52. 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
Ester + H20 Acid + Alcohol
Esterase

53. Phase I – contd.
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

54. 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

55. Phase II metabolism – contd.
 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

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

57. 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

58. Microsomal 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 or duration of action of drugs – Failure of OCPs
 Increased intensity – Paracetamol poisoning
 Tolerance – Carbmazepine (if the drug induce its own metabolism)
 Some endogenous substrates are metabolized faster – steroids, bilirubin

59. 4. Excretion

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

61. 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
Portal
vein
Bile duct
Intestines

62. Renal Excretion
Glomerular Filtration
Tubular Reabsorption
Tubular Secretion

63. 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

64. Tubular Re-absorption
 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.

65. 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)
 OATP – organic acid transport
 OCT – organic base transport
 P-gp
 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

66. Renal Excretion
Acidic urine
 alkaline drugs eliminated
 acid drugs reabsorbed
Alkaline urine
- acid drugs eliminated
- alkaline drugs absorbed

67. Kinetics of Elimination
 Pharmacokinetics - F, V and CL
 Clearance: The clearance (CL) of a drug is the
theoretical volume of plasma from which drug is
completely removed in unit time
CL = Rate of elimination (RoE)/C
Example = If a drug has 20 mcg/ml and RoE is 100
mcg/min
CL = 100/20 = 5 ml /min

68. Kinetics of Elimination
 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 etc.

69. 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
t1/2 = 0.693 x V / CL
CL = RoE/C
V = dose IV/C

70. Plasma half-life
1 half-life …………. 50%
2 half-lives………… 25%
3 half-lives …….…..12.5%
4 half-lives ………… 6.25%
50 + 25 + 12.5 + 6.25
= 93.75
93.75 + 3.125 + 1.56 =
98% after 5 HL

71. Excretion - The Platue Principle
Repeated dosing:
• When constant dose of a drug is repeated
before the expiry of 4 half-life – peak
concentration is achieved after certain
interval
• Balances between dose administered and
dose interval

72. Repeated Dosing
 At steady state, elimination = input
Cpss = dose rate/CL
Dose Rate = target Cpss x CL
In oral administration
Dose rate = target Cpss x CL/F
In zero order kinetics: follow Michaelis Menten
kinetics
RoE = (Vmax) (C) / Km + C
Vmax = max. rate of drug elimination, Km = Plasma
conc. In which elimination rate is half maximal
CL = Roe/C

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
 Loading dose = target Cp X V/F
 Maintenance dose: dose to be repeated at specific intervals

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
etc
 Drugs activated in body – levodopa
 Hit and run drugs – Reseprpine, MAO inhibitors
 Irreversible action drugs – Orgnophosphorous compounds

75. Summary – Must Know
 Definition of Pharmacokinetics
 Transport of Drugs across Biological Membrane – different processes
with example
 Factors affecting absorption of drugs
 Concept of Bioavailability
 Distribution of Drugs – Vd and its concept
 Biotransformation Mechanisms with examples
 Enzyme induction and inhibition concept and important examples
 Routes of excretion of drugs
 Orders of Kinetics
 Definition and concept of drug clearance
 Definition of half life and platue principle

76. 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