Pharmacokinetics study

1. Pharmacokinetics
SAIYAD ARSH ZIA
Department of Pharmacology

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
Dosage Regimen
Concentration in Plasma
Concentration at the site of
action
Absorption
Distribution
Metabolism
Excretion
Pharmacokinetics
Pharmacodynamics
Effect

4. The Pharmacokinetic Process

5. The Pharmacokinetic Process

6. Biological Membrane - image

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

8. 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
• Proportional to lipid : water partition coefficient
• Lipid soluble drugs diffuse by dissolving in the lipoidal matrix of the
membrane
• Characteristics
– Not requiring energy
– Having no saturation
– Having no carriers
– Not resisting competitive inhibition

9. Passive transportAffecting 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

10. 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.

11. pH Effect
• Most of drugs are weak acids or weak bases.
• The ionization of drugs may markedly reduce
their ability to permeate membranes.

12. Implications
• Acidic drugs re absorbed are largely unionized in
stomach and absorbed faster while basic drugs are
absorbed faster in intestines
• 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 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

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)

18. Pinocytosis
• 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. Pinocytosis is
important for the transport of some
macromolecules (e.g. insulin through BBB).

19. 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

20. 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):

21. Factors affecting absorption – contd.
Route of administration:
• Topical:
– Depends on lipid solubility – only lipid soluble drugs are
penetrate intact skin – only few drugs are used therapeutically
– Examples – Hyoscine, Nicotine, testosterone and estradiol
– Mucus membranes of mouth, rectum, vagina etc, are
permeable to lipophillic drugs

22. Factors affecting absorption – contd.
Route of administration:
• 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

23. Factors affecting absorption – contd.
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

24. 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.

25. 1st
pass Elimination – Metabolism in liver
Buccal cavity
Stomach
Intestine
Rectum
Portal
vein
Vena
cava

26. Buccal and Rectal – bypasses liver
Vena
cava

27. Absorption – contd.
• Intravenous administration has no absorption
phase
• According to the rate of absorption:
Inhalation→Sublingual→Rectal→intramusc
ular→subcutaneous→oral
Example – Nitroglycerine:
IV effect – immediate, SL – 1 to 3 min and

28. 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.

29. Biovailability - AUCPlasmaconcentration
(mcg/ml)
Time (h)0 5 10 15
AUC p.o.
F = ------------ x 100%
AUC i.v.
AUC – area under the
curve
F – bioavailability

30. 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, disease like CHF,
uremia, cirrhosis
• Movement of drug - until equilibration between unbound
drug in plasma and tissue fluids

31. 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

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

33. Volume of Distribution (V)
Vd = IV dose/C

34. 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

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

36. 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. A similar barrier is loctated in the choroid
plexus
Brain and CSF Penetration

37. 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.
(Inflammation of meanings of brain increases permeability of BBB)
• Dopamine (DA) does not enter brain, but its precursor levodopa
does. This is used latter in parkinsonism.

38. 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

39. 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.

40. 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).

41. Tissue storage
Drugs may also accumulate in specific organs or get bound to specific tissue
constituents, e.g.:
• Heart and skeletal muscles – digoxin (to muscle proteins)
• Liver – chloroquine, tetracyclines, digoxin
• Kidney – digoxin, chloroquine
• Thyroid gland – iodine
• Brain – chlorpromazine, isoniazid, acetazolamide
• Retina – chloroquine (to nucleoproteins)
• Iris – ephedrine, atropine (to melanin)
• Bones and teeth – tetracyclines, heavy metals (to mucopolysaccharide of
connective tissue)
• Adipose tissues – thiopental, ether, minocycline, DDT

42. 3. Biotransformation
Metabolism of Drugs

43. 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

44. 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 and prednisone – prednisolone)
4. No toxic or less toxic drug to toxic metabolites (Isonizide to
Acetyl isoniazide)
(Mutagenicity, teratogenicity, carcinogenicity, hepatotoxicity)

45. 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)

46. 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

47. 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
• 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

48. Oxidation - CYP
CYP3A4/5

49. Nonmicrosomal Enzyme Oxidation
• Some Drugs are oxidized by non-microsomal
enzymes (mitochondrial and cytoplasmic) –
• Alcohol – Dehydrogenase
• Adrenaline – MAO
• Mercaptopurine – Xanthine oxidase

50. 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. Phase I - Hydrolysis
• This is cleavage of drug molecule by taking up of a molecule of water.
• Hydrolysis occurs in liver, intestines, plasma and other tissues.
• Examples - Choline esters, procaine, lidocaine, pethidine, oxytocin

52. 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

53. 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

54. Phase II metabolism – contd.
• Acetylation: Compounds having amino or hydrazine
residues are conjugated with the help of acetyl CoA,
e.g.sulfonamides, isoniazid
• Sulfate conjugation: The phenolic compounds and
steroids are sulfated by sulfokinases, e.g.
chloramphenicol, adrenal and sex steroids

55. Phase II metabolism – contd.
• Methylation: The amines and phenols can be
methylated. Methionine and cysteine act as methyl
donors.
– Examples: adrenaline, histamine, nicotinic acid.

56. Factors affecting Biotransformation
• Factors affecting biotransformation
– Concurrent use of drugs: Induction and inhibition
– 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 boiled meat,
industrial pollutants – CYP1A

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
Intesti
nes

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
• 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)
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 -
• 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. Kinetics of Elimination
Zero Order 1st Order
con
c.
Time

70. 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

71. 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

72. 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

73. 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

74. 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

75. 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

76. 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

77. 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

78. THANK YOU
SAIYAD ARSH ZIA