www.linkedin.com/in/dr-aboobecker-siddique-p-a-200783a0 pharmacokinetics 2 fate of a drug biotransformation : Chemical alteration of the drug in a living organism is called bio-transformation. Lipid soluble →Water soluble So that not reabsorbed in Kidney Site-Mainly liver Others-Kidney, lungs, plasma, gut mucosa & skin metabolism xenonbiotics microsomal enzyme induction excretion kinetics of elimination

1. Fate of the drug
Dr. Ab.Siddique.P.A
Associate Professor
Pharmacology & Therapeutics

2. Biotransformation:Metabolism
• Chemical alteration of the drug in a
living organism is called bio-
transformation.
• Lipid soluble →Water soluble
So that not reabsorbed in Kidney
• Site-Mainly liver
• Others-Kidney, lungs, plasma, gut
mucosa & skin

3. Biotransformation
• Morphine, chloramphenicol
Active drug to
inactive
metabolite:
• Primidone → phenobarbitone
• Digitoxin → digoxin
• Diazepam → oxazepam
Active drug to
active
metabolite:
• Levodopa → dopamine
• Prednisone → prednisolone
• Enalapril → enalaprilat
Inactive drug to
active metabolite
(pro-drug):

4. Metabolism: Consequences
• End result is usually inactivation of a drug-
But intermediate product need not be!
Active → Toxic. Eg. P.Mol →NABQI

5. Metabolism:Phases: I & II
Most drugs are metabolized by
many pathways, simultaneously or
sequentially –producing a variety
of metabolites
Phase II
(Eg.INH)
Phase I Metabolite

6. Enzymes in biotransformation
• Phase I: (non-synthetic reactions):
– Convert the drug to a more polar metabolite by
oxidation, reduction or hydrolysis
– Oxidation reactions: Most important metabolizing
reactions, catalysed by mono-oxygenases present
in liver
– If metabolite is not sufficiently water- soluble to
be excreted → phase II

7. Biotransformation…
• Phase II (synthetic reactions)
– Water-soluble substances present in the body like
glucuronic acid, sulfuric acid, glutathione or an
amino acid + drug (or its phase I metabolite) ⇒
highly polar compound
– inactive& gets readily excreted by kidney

8. Biotransformation
Administered drug
[Lipid soluble]
[Non-Polar]
[Lipophilic]
Excreted
[water soluble]
[Polar]
[Hydrophilic]
By
Phase I and Phase II reactions
Catalyzed by enzymes
Microsomal and Non-microsomal enzymes

9. Metabolism:Phase I[Non-synthetic]
1. Oxidation:
Addition of O2/Removal of H+
Eg. Phenytoin, Phenobarbitone, Propranolol
2. Reduction:
Opp.of Oxidation
Eg. Choramphenicol, Methadone
3. Hydrolysis:
Addition of water
Eg.Esters-Procaine, Succinylcholine,
Amides- Procainamide, Lignocaine
4. Others-Cyclization and decyclization

10. Metabolism:Phase II(Synthetic)
• Conjugation of a drug or phase I
metabolite with endogenous substrate –
Glucuronic acid, Sulfuric acid, Acetic acid-
Making it water soluble for excretion.
Glucuronide conjugation Eg.Morphine, Paracetamol
Acetylation Eg.INH, Dapsone
Glycine conjugation Eg.Salicylic acid, Nicotinic
acid
Sulphate conjugation Eg.Sex steroids
Glutathione conjugation Eg.Paracetamol
Methylation Eg.Adrenaline, Dopamine

11. Biotransformation:Catalyzed by Enzymes
Microsomal Non-Microsomal
 In endoplasmic
reticulum
 Most of Phase I and
some Phase II
[Glucuronide
conjugation]
 Inducible
 CYP450
 Eg. CYP2D6
• Cytoplasm, Mitochondria
of liver cells and plasma
• Most of Phase II and
some Phase I [Some
oxidation, most
reduction and hydrolysis]
• Not inducible
• Genetic polymorphism
• Flavoprotein oxidases,
esterases, amidases

12. Enzyme induction
• Microsomal enzymes present in liver
• Synthesis of these enzymes enhanced by
certain drugs & environmental pollutants
• Enzyme induction
– Speeds up the metabolism of inducing drug itself &
other drugs metabolised by microsomal enzymes
E.g. phenobarbitone, rifampicin, alcohol,
cigarette smoke, DDT, griseofulvin,
carbamazepine & phenytoin

13. Clinical importance
• Drug interactions: e.g. failure of oral
contraceptives in patients taking
rifampicin
• Toxicity: e.g. patient on rifampicin likely
to develop hepatotoxicity with
paracetamol
• Tolerance to drugs : carbamazepine
induces its own metabolism
• Beneficial –Phenobarbitone in newborn
jaundice, liver disease, chronic poisoning

14. Clinical importance
• Endogenous substrates like steroids,
bilirubin are also metabolized faster
• Precipitation of acute intermittent
porphyria
• Interferes with dose adjustments of
regularly taken drugs

15. Enzyme inhibition
• Drugs inhibit microsomal enzyme
activity
• Drugs like cimetidine & ketoconazole
bind to these enzymes ⇛ competitively
inhibit metabolism of testosterone &
other drugs
• Enzyme inhibition leads to drug
interactions
– Chloramphenicol, erythromycin, cimetidine,
ketoconazole, ciprofloxacin & verapamil

16. Factors affecting Biotransformation
1. Age-Extremes of age enzymes may be
deficient Eg.Chloramphenicol in premature
babies causes Gray baby syndrome.
2. Malnutrition:- metabolism due to  enz.
proteins.
3. Liver disease:-  metabolism-- … so..dose of
drug
4. Genetic: Genetically determined variation in
metabolism
 Slow and fast acetylators-INH
 SCH

17. Prodrug
• Inactive drug
• Converted to active form by metabolism
• Improved B.A.-L-Dopa and Dopamine
• Prolongs duration of action- Fluphenazine
• Improves taste- Clindamycin palmitate
• Methenamine release Formaldehyde in
acidic urine

18. First pass metabolism
• Metabolism of a drug during its passage from
the site of absorption to the systemic
circulation-liver, intestines, skin or lungs
– Presystemic metabolism or first pass effect
• Extent of absorption differs from drug to
drug & person to person
• May lead to
– Partial inactivation: compensated by increasing
dose e.g. nitroglycerine, propranolol, salbutamol
– Total inactivation: route has to be changed e.g.
isoprenaline, hydrocortisone, insulin

19. First pass
metabolism
• Important feature of oral
route –oral dose higher
than parenteral dose
• Marked inter-individual
variations
• Oral bioavailability⇛⇧
liver disease
• Oral bioavail.⇧⇨
Concurrent admin. Of
another drug which
competes for first pass
metabolism

20. Drug Excretion
Removal of drug and its metabolites
from body
• Kidney
• Lungs
• Bile
• Feces
• Sweat
• Saliva
• Tears
• Milk

21. Excretion-Kidney
Renal
excretion
Glomerular
Filtration
Tubular
secretion
Tubular
reabsorption

24. Glomerular Filtration
• Mol.size
• Depends on Renal blood
flow
• Plasma protein binding

25. Tubular reabsorption
• Acidic drugs ionise in alkaline urine→ easily
excreted
• Bases are excreted faster in acidic urine
• Forced alkaline diuresis: (diuretic + sodium
bicarbonate + IV fluids) employed to promote
drug excretion in poisoning with acidic drugs
like salicylates & barbiturates
• Elimination of basic drugs like quinine &
amphetamine enhanced by forced acid
diuresis

26. Tubular secretion-Active
• Carrier mediated
• Not affected by PPB
• Penicillin, Probenecid, Quinine
• May use same carrier-Non-
specific
• Probenecid inhibits penicillin
secretion

27. Tubular secretion
• Thiazide diuretics may compete
with uric acid → uric acid is
reabsorbed → elevated uric acid
levels→ gouty arthritis; hence
thiazides are contraindicated in
gout
• Salicylates block uricosuric action
of Probenecid

28. Faecal & biliary excretion
• Unabsorbed part of orally administered drugs
→ excreted in faeces
• Liver transfers acids, bases & unionized
molecules into bile by specific transport
processes
• Water-soluble conjugates → excreted in bile
• Enterohepatic circulation: Some drugs get
reabsorbed in lower portion of gut → liver
– Prolongs duration of action
– E. g. chloramphenicol, tetracycline, oral
contraceptives, erythromycin

29. Other routes of excretion
• Pulmonary excretion
– Lungs: main route for gases, volatile liquids
(general anaesthetics & alcohol)
• Excretion of drug in saliva → unique taste
– E.g. metronidazole, phenytoin
• Drugs like iodide, rifampicin & heavily metals
→ excreted in sweat
• Excretion in milk: small amounts; no
significance to mother; may harm infant
• Griseofulvin, mercury & arsenic excreted
through hair & nails

30. Factors affecting renal excretion

31. Kinetics of Elimination
Clearance
THE CLEARANCE OF A DRUG IS THE
THEORETICAL VOLUME OF PLASMA
FROM WHICH THE DRUG IS
COMPLETELY REMOVED IN UNIT TIME.
Rate of elimination
CL= …………………………
Plasma conc.( C)

33. Clearance
• Time required for complete elimination
of administered dose of a drug
• Direct expression of the body’s ability
to eliminate drug
• Dependent on blood flow to the organs
of excretion, protein binding, plasma
conc, hepatic & renal diseases
• In renal diseases reduction of dosage &
less frequent administration required
• Useful in predicting response in a given
condition

34. PLASMA HALF LIFE- t1/2
It is the time required for the plasma
conc. of the drug to be reduced to half of
its original value.

35. 100
50
150
75
175
87.5
187.5
93.5
193.5
96.5
196.5
98
198
99
199
100
Takes 4-5 half lives to reach steady state concn.
Steady state
[Plataeu principle]

36. Elimination First order
100 mg administered[100%]
• 1 t1/2 50mg 50%
• 2 t1/2 25mg 75%
• 3t1/2 12.5 mg 87.5%
• 4t1/2 6.25.mg 93.75%
• Take 4-5 half lives for complete
elimination of a drug

37. Factors Influencing Drug dosage
• 4-5 half lives for steady state
• Short half life → repeated admn.
• Long half life→Takes long time to
reach steady state
• So loading dose is given for
immediate effect
• Maintainance dose is given to
maintain steady state

38. Plasma half life (t1/2)
• Indicates duration of action; index of plasma
conc.
• Rate at which drug is eliminated depends on
volume of distribution & clearance
• Estimate to determine appropriate dosing
interval
• Indicator of time required to attain steady
state plasma conc.
• Depends on severity of disease, age, protein
binding, tissue binding & rate of absorption

39. Elimination: First and Zero Order Kinetics
A constant Fraction of the drug in the body is
eliminated per unit time-
First order kinetics: Most drugs
A constant Amount of the drug in the body is
eliminated per unit time-
Zero order kinetics: Alcohol
To start with First order→As the plasma concn.increases →Zero
order←Enzymes get saturated………
Saturation kinetics. Eg.Phenytoin

40. First order kinetics
• Rate of drug administration equals rate
of elimination → drug concentration in
plasma is steady
• Drug dose is directly proportional to
steady state plasma conc.
• Doubling the dose → two-fold increase
in plasma conc.
• Relationship between dose & rate of
excretion is linear

41. Zero order kinetics
• Non-linear relationship between dose &
plasma steady state conc
• Also called non-linear or saturation kinetics
• E.g. Phenytoin, alcohol, heparin
• Clinical significance:
– Chances of accumulation
– Difficulty to attain steady state concentration in
plasma due to variations in kinetics from individual
to individual
– Necessitates plasma concentration monitoring →
Therapeutic drug monitoring

42. Therapeutic drug monitoring-TDM
• Monitoring drug therapy by measuring plasma
conc.of drugs.
• Indications
1. Drugs with low margin of safety-
Digoxin,Lithium
2. To check Pt. compliance.
3. If individual variations are large.- TCA.
4. Potentially toxic drugs used in presence of
renal failure-AMINOGYCOSIDES
5. When Pt. does not respond without reason

43. Fixed dose combinations
• Combination of 2 or more drugs in a
single formulation
– Levodopa + carbidopa in parkinsonism
– Isoniazid + Rifampicin + Pyrazinamide in
tuberculosis
– Ferrous sulphate + folic acid in anaemia
– Trimethoprim + Sulfamethoxazole as C
otrimoxazole
– Oestrogen + Progesterone as oral
contraceptive

44. Fixed dose combination
Advantages
• Better patient
compliance
• Synergistic effect
• Increased efficacy
• Reduced side effect
• Reduced cost
• Prevents resistance
Disadvantages :
• Inflexible fixed
dose ratio
• Incompatible
pharmacokinetics
• Increased toxicity
• Physician &
Pharmacist’s
ignorance of
contents

45. Methods to prolong duration of
action
For orally administered drugs:
• Enteric coated forms e.g. erythromycin
• Sustained release preparations e.g.
diclofenac

46. Methods to prolong drug action
For parenterally administered drugs:
• Decreasing the vascularity of absorbing
surface
• Decreasing solubility
• Injecting in oily solution
• Pellet implantation
• Ocusert/progestasert/transdermal patch
• Increasing plasma protein binding
• Inhibiting drug metabolism
• Delaying renal excretion

47. Drug dosage
• Posology : Branch of Pharmacology which
deals with doses
• Therapeutic dose : Quantity of the drug
required to produce therapeutic effect
• Minimum dose: Smallest dose required to
produce desired therapeutic effect
• Maximum dose: Largest dose that can be
safely given without harmful effects
• Toxic dose: Dose which produces toxic
effects in majority of patients

48. Drug dosage
• Lethal dose: dose which can cause death
• Fixed dose: fixed amount of drug is usually
suitable for most of the patients e.g.
Paracetamol 500mg 6 hrly
• Individualising dose: in drugs with low safety
margin dose is individually tailored to meet
the required need e.g. anticonvulsants,
antiarrhythmics

49. Drug dosage..
• Loading dose: In situations where target
plasma conc. have to be attained rapidly
loading/bolus dose is given
– Single large dose or series of quickly repeated
doses given rapidly to attain target concentration
– E.g. heparin given as 5000IU bolus dose
• Maintenance dose: drug given in a dose
to sufficiently maintain plasma levels &
to balance elimination
– Disadvantage: rapid exposure to high dose →
toxicity