metabolism and excretion

1. Biotransformation
and
elimination
By Maheshwari Hireholi
Mpharm 1st year

2. OVERVIEW
• Definition
• Consequences
• Types
• Phase I and II reactions
• Enzyme induction/inhibition
• First pass metabolism
• Excretion
• Types
• Factors affecting excretion
• Kinetics of elimination

3. Definition
• Chemical alteration of drug in the body.
• Non polar lipid soluble compounds are made polar
lipid insoluble, so that they are easily excreted.
Biotransformation is needed for
detoxification & protect the body from ingested
toxins.

4. SITES
• Primary site – Liver
• Others – Kidney, Intestine, Lungs, Plasma…

5.  Biotransformation normally leads in
pharmacological inactivation of drugs
Ex: conversion of phenytoin to p-hydroxy
phenytoin,
 occasionally yields metabolites with equal
activity
ex: conversion of phenylbutazone to
oxyphenbutazone

6. Rarely leads to toxicological activation of
drugs
Ex : conversion of paracetamol to reactive
metabolites that cause hepatic necrosis.
Activation of inactive drug
Ex : Digitoxin to Digoxin, Primidone to
Phenobarbitone.

7. Absorbed drugs – undergo mainly
three changes
Metabolic changes by Enzymes ( Microsomal, Cytoplasmic,
Mitochondrial)
Spontaneous Molecular rearrangement – HOFMANN
ELIMINATION (This refers to inactivation of the drug in
the body fluids by spontaneous molecular rearrangement
without the agency of any enzyme, e.g. Atracurium)
Excreted unchanged (highly polar drugs) -
Aminoglycosides, Methotrexate,Neostigmin

8. CONSEQUENCES
A) Drug inactivation - inactive or less active
Propranolol, Pentobarbitone,
Chloramphenicol, Paracetamol, Ibuprofen,
lignocaine
B) Active drug to Active metabolite- active
metabolite
Ex: Phenacetin to Paracetamol

9. C) Inactive drug (Prodrug) - Active drug Prodrugs
are inactive drugs which need BT in the body
to form active metabolites.
ADVANTAGE:
More stable
Better BA
Less toxicity

10. Active drug Active metabolite
Chloral hydrate Trichloroethanol
Morphine Morphine-6-glucuronide
Cefotaxime Desacetyl cefotaxime
Allopurinol Alloxanthine
Procainamide N-acetyl procainamide
Primidone Phenobarbitone
Diazepam Desmethyl-diazepam, oxazepam
Imipramine Desipramine
Amitriptyline Nortriptyline
Codeine Morphine
Spironolactone Canrenone

11. TYPES
Phase I / Non synthetic / Functionalization
• A functional group is generated
• Catabolic reaction
• Metabolite – active or inactive
Phase II / Synthetic / Conjugation
• An endogenous radical is conjugated
• Anabolic
• Metabolite is usually inactive

12. Phase I Reactions
• Oxidation
• Reduction
• Hydrolysis
• Cyclization
• Decyclization

13. Phase II Reactions
• Glucuronide conjugation
• Acetylation
• Methylation
• Sulfate conjugation
• Glycine conjugation
• Glutathione conjugation
• Ribonucleotide / Ribonucleoside synthesis

14. a) OXIDATION
• Addition of Oxygen / negatively charged
radical or removal of Hydrogen / Positively
charged radical
• Oxidation is the main process of metabolism
• Produces unstable intermediates - Epoxides,
Superoxides, Quinones
• Oxidation – 9 types

15. 1.OXIDATION AT NITROGEN ATOM
RNH2 o RNHOH
• Chlorpheniramine
• Dapsone
• Meperidine

16. 2.OXIDATION AT SULPHUR ATOM
• Chlorpromazine
• Chloramphenicol

17. 3.ALIPHATIC HYDROXYLATION
• Hydroxyl group added to drug
RCH2CH3 O RCHOHCH3
• Salicylic acid to Gentisic acid
• Ibuprofen
• Tolbutamide, Chlorpropamide,

18. 4.AROMATIC HYDROXYLATION
• Phenytoin
• Phenobarbitone
• Propranolol

19. 5.DEALKYLATON AT OXYGEN ATOM
ROCH3 O ROH + CH2O
• Phenacetin to Paracetamol

20. 6.DEALKYLATON AT NITROGEN ATOM
RNHCH3 O RNH2 + CH2O
• Amitriptyline to Nortriptyline

21. 7.DEALKYLATON AT SULPHUR
ATOM
• 6-Methyl thiopurine to Mercaptopurine

22. 8.OXIDATIVE DEAMINATION
• Amphetamine

23. 9.DESULFURATION
• Parathion to Paraoxon
The main enzymes involved in phase I
reaction are ooxygenases.

24. b) REDUCTION
• Addition of Hydrogen / positively charged radical
or removal of Oxygen / negatively charged radical
• MICROSOMAL REDUCTION by
Monooxygenases need NADPH & cytochrome c
reductase.
A.NITRO Reduction
RNo2 RNH2
• Chloramphenicol to aryl amine metabolite
B.KETO Reduction
Cortisone to Hydrocortisone

25. c. Azo reduction
• Prontosil to Sulfanilamide
• NON MICROSOMAL REDUCTION
Chloral hydrate to Trichloro ethanol,

26. c) HYDROLYSIS
• Drug is split combining with water
• Ester + water Esterases Alcohol & Acid
• Microsomal hydrolysis
Pethidine to meperidinic acid
• Non microsomal hydrolysis
Esterases,Amidases & Peptidases
Atropine to Tropic acid

27. d) CYCLIZATION
• Formation of ring structure from a straight
chain compound. Eg: Proguanil

28. e) DE CYCLIZATION
Ring structure is opened
• Phenytoin, Barbiturates

29. PHASE II REACTIONS /Synthetic
reactions
• Involve transfer of a suitable moiety such as
glucuronic acid, sulfate, glycine, etc, in
presence of enzyme transferases to drugs or
metabolites of phase I reaction having suitable
functional groups to form highly polar n
readily excretable conjuagtes.
• Phase II- need energy

30. 1.CONJUGATION WITH GLUCURONIC
ACID
• Carried out by UDP glucuronyl transferases
• Compounds with OH & COOH are easily
conjugated with glucuronic acid derived from
glucose
Drug + UDPGA Microsomal Glucuronyl
transferase Drug glucuronide + UDP
• Drugs - Aspirin,Paracetamol,PABA,
Metronidazole, Morphine, Diazepam

31. • ↑Mol. Weight – favours biliary excretion
• Drug glucuronides excreted in bile are
hydrolyzed by intestinal microfloral enzymes -
parent drug released - reabsorbed into
systemic circulation- ↓excretion ↑duration of
action - Oral contraceptives, Phenolphthalein
• Endogenous substrates - Steroid, Thyroxin,
Bilirubin

32. 2. ACETYLATION
• Drugs with Amino or Hydrazine groups - INH,
PAS,Hydralazine, Sulfonamides
,Procainamide, Dapsone.
• Genetic polymorphism
• Acetylation- Rapid / Slow

33. 3. CONJUGATION WITH SULFATE
• Drug groups-Amino, Hydroxyl
• Cytoplasmic Enzymes - Sulfotransferases /
Sulfokinases.
• Methyl dopa, Steroids, Chloramphenicol,
Warfarin
• The phenolic compounds and steroids are
sulfated by sulfotransferases (SULTs).

34. 4. CONJUGATION WITH GLYCINE
• Drugs having Carboxylic group
• Salicylic acid , Benzoic acid

35. 5. Conjugation with glutathione
• Drug groups- Epoxide, Quinone
• Toxic metabolites of Paracetamol, Ethacrynic
acid
• Cytoplasmic Enzyme - Glutathione S-
Transferase

36. 6. METHYLATION
• Drugs with Amino & Phenol groups
• Histamine, Adrenaline, Nicotinic acid,
Dopamine, Methyl dopa, Captopril
• Enzyme- Methyl transferase
• Endogenous substance- Cysteine, Methionine

37. 7. RIBONUCLEOTIDE/RIBONUCLEOSIDE
SYNTHESIS
• Action of Purine & Pyrimidine antimetabolites
• 6 Mercaptopurine

38. Enzymes involved
Microsomal enzymes
located on SER, primarily in liver, also in
kidney, intestinal mucosa and lungs.
Ex : monooxygenases, cytchrome P450,
glucuronyl transferase etc,.
Catalyse most of the oxidation, reduction,
hydrolysis and glucuronide conjugation.
Induced by drugs, diet and agencies.

39. Non-microsomal enzyme
Present in cytoplasm and mitochondria of hepatic
cells, as well as in other tissues including plasma.
Ex : flavoprotein oxidases, esterases, amidases
and conjugases.
Reaction catalysed are oxidation, reduction, many
hydroytic and all conjugation except
glucuronidation.
• These are not inducible but many show genetic
polyphorism( acetyl transferases)

40. Microsomal enzyme induction
Drugs, insecticides, carcinogens will induce
the synthesis of microsomal enzyme proteins.
Accelerated metabolism and reduced
pharmacological response.

41. Consequences
1. Decreased intensity and/or duration of action of drugs that are inactivated by
metabolism, e.g. failure of contraception with oral contraceptives.
2. Increased intensity of action of drugs that are activated by metabolism.
Acute paracetamol toxicity is due to one of its metabolites—toxicity occurs
at lower doses in patients receiving enzyme inducers.
3. Tolerance—if the drug induces its own metabolism (auto induction), e.g.
carbamazepine, rifampin.
4. Some endogenous substrates (steroids, bilirubin) are also metabolized faster.
5. Precipitation of acute intermittent porphyria: enzyme induction increases
porphyrin synthesis.
6. Intermittent use of an inducer may interfere with adjustment of dose of
another drug prescribed on regular basis, e.g. oral anticoagulants, oral
hypoglycaemics, antiepileptics, antihypertensives.
7. Interference with chronic toxicity testing in animals

42. FIRST PASS (PRESYSTEMIC)
METABOLISM
• This refers to metabolism of a drug during its passage
from the site of absorption into the systemic
circulation.
• ↓ed BA
• ↓ed therapeutic response
• SITES
* Gut wall
*Gut lumen
*Liver (major site)
*Lungs
*Skin

43. Excretion
• It is the process where by drug or their
metabolite are irreversibly transferred from
internal to external environment through
renal or non renal route.
• The principle organ of excretion are kidneys.

44. Types of excretion
1. RENAL EXCRETION
2. NON RENAL EXCRETION
a. Biliary excretion
b. Pulmonary excretion
c. Salivary excretion
d. Mammary excretion
e. Skin/ dermal excretion
f. Gastrointestinal excretion

45. RENAL EXCRETION
• The kidney is responsible for excreting all
water soluble substances.
• Net renal excretion =(Glomerular filtration +
tubular secretion) – tubular reabsorption

47. GLOMERULAR FILTRATION
• It Is non selective , unidirectional process
• Ionized or unionized drugs are filtered, except
those that are bound to plasma proteins.
• Driving force for GF is hydrostatic pressure of
blood flowing in capillaries.
• Glomerular filtration rate (g.f.r.), normally ~
120 ml/min, declines progressively after the
age of 50, and is low in renal failure.

48. ACTIVE TUBULAR SECRETION
• This mainly occurs in proximal tubule.
• It is carrier mediated process which requires energy for
transportation of compounds against conc. gradient
Two secretion mechanisms are identified.
• System for secretion of organic acids/anions E.g.
Penicillin, salicylates etc
• System for organic base / cations E.g. morphine,
mecamylamine hexamethonium
• Active secretion is Unaffected by change in pH and
protein binding.
• Drug undergoes active secretion have excretion rate
values greater than normal GFR e.g. Penicillin.

49. TUBULAR REABSORPTION
• It occurs after the glomerular filtration of
drugs. It takes place all along the renal
tubules.
• Reabsorption of drugs indicated when the
excretion rate value are less than the GFR
130ml/min. e.g. Glucose
• TR can be active or passive processes.
• Reabsorption results in increase in the half
life of the drug.

50. Active Tubular Reabsorption
Its commonly seen with endogenous
substances or nutrients that the body needs to
conserve e.g. electrolytes, glucose, vitamins.
• Passive Tubular Reabsorption
It is common for many exogenous substances
including drugs. The driving force is Conc.
Gradient which is due to re-absorption of water,
sodium and inorganic ions. I

51. FACTORS AFFECTING RENAL
EXCRETION
• Physicochemical properties of drug
• Urine pH
• Blood flow to the kidney
• Biological factor
• Drug interaction
• Disease state

52. KINETICS OF ELIMINATION
There are three fundamental pharmacokinetic
parameters, viz. bioavailability (F), volume of
distribution (V) and clearance (CL) which must
be understood. The first two have already
been considered.

53. Clearance
• Is defined as the hypothetical volume of body
fluids containing drug from which the drug is
removed/ cleared completely in a specific
period of time. Expressed in ml/min.
• CL = Rate of elimination/C

54. TOTAL BODY CLEARANCE
Is defined as the sum of individual clearances by all
eliminating organs is called total body clearance/ total
systemic clearance
Total body clearance= CLliver+ CLkidney+ CLlungs+CLx

55. Plasma half-life
• The Plasma half-life (t½) of a drug is the time
taken for its plasma concentration to be reduced
by half of its original value.
• Mathematically, elimination t½ is
t½ = ln2 /t½
• Where ln2 is the natural logarithm of 2 (or 0.693)
and k is the elimination rate constant of the drug,
i.e. the fraction of the total amount of drug in the
body which is removed per unit time.

56. Half life of some representative drugs
• Aspirin 4 hr
• Digoxin 40 hr
• Penicillin-G 30 min
• Digitoxin 7 days
• Doxycycline 20 hr
• Phenobarbitone 90 hr

57. Repeated drug administration
• When a drug is repeated at relatively short
intervals, it accumulates in the body until
elimination balances input and a steady state
plasma concentration (Cpss) is attained,
Cpss=dose rate/CL
• After oral administration, often only a fraction (F)
of the dose reaches systemic circulation in the
active form. In such a case—
dose rate=target Cpss× CL/F

58. Loading dose
• The loading dose is one or a series of doses that
may be given at the onset of therapy with the aim
of achieving the target concentration rapidly.
• The appropriate magnitude for the loading dose is
Loading dose=target Cp × V L/ F
• loading dose is governed only by V and not by CL
or t½.

59. Maintenance dose
• This dose is one that is to be repeated at
specified intervals after the attainment of target
Cpss so as to maintain the same by balancing
elimination.
• The maintenance dose rate is computed by
equation
dose rate=target Cpss× CL/F
• and is governed by CL (or t½) of the drug.

60. Reference
• Goodman and Gilman’s.(2011) ‘The
Pharmacological Basis of Therapeutics’.26-30.
• Tripati.K.D.(2013) ‘ Essentials of medical
Pharmacology’ , 22-36.
• Brahmankar.D.M, Jaiswal.B. Sunil.(2008)
‘Biopharmaceutics and Pharmacokinetics’
,111-157.