drug metabolism-Biopharmaceutics

1. WELCOME TO
SEMINAR
ON
DRUG METABOLISM

2. SEMINAR
ON
DRUG METABOLISM
UNDER THE GUIDANCE OF
K.SRIKANTH GUPTA
BY ASST.PROFESSOR
SAMEERA PRIP
M-PHARMACY -1YR
(PHARMACEUTICS) UNDER THE CO-GUIDANCE OF
11CM1S0313 V.RAMA MOHAN GUPTA
PRIP. PRINCIPAL & HOD
PRIP

3. CONTENTS
INTRODUCTION TO METABOLISM
1
2 DRUG METABOLISM INTRODUCTION
3 SITES OF DRUG METABOLISM
4 METHODS FOR STUDY OF DRUG
METABOLISM
5
6

5. INTRODUCTION
TO
METABOLISM
Sum total of all the enzyme –catalyzed
reactions that occur in an organism.

6. METABOLIC PATHWAYS

7. TYPES OF METABOLISM

8. IMPORTANCE OF METABOLISM
 To obtain chemical energy
 To synthesize complex molecules
 To convert nutrient molecule into its precursor form
for future use

10. •What is drug metabolism?
•Importance of drug metabolism? Why it is
necessary?
•How it will takes place?
•Where it will takes place?(sites of drug metabolism)
•When it will takes place ?

11. WHY DRUG METABOLISM IMPORTANT?
 Drugs are mostly lipid soluble, easy to cross membranes, bind to plasma
proteins & reabsorb from renal tubules
 Metabolism changes them to water soluble & easily excretable products; also
become inactive or less active

12.  Termination of drug action
 .Activation of prodrug
 .Bioactivation and toxication
 .Carcinogenesis
 Tetratogenesis

13. Termination of Drug Action
Conversion of drug to active metabolite to active metabolite to
inactive metabolite
• Parent compound inactive metabolite
Atropine tropic acid & tropin
propranolol hydroxyl propranolol

14.  Inactive active
parent compound metabolite
Eg: Levodopa dopamine

15. Some Xenobiotics Are Metabolized to
Carcinogenic Agents
• 3,4 Benzopyrene
• Aflatoxin
• N-Acetylaminofluorene
Metabolites of these agents interact with DNA

16. Small Amounts of Acetaminophen is Converted to the
Reactive Metabolite N-Acetyl benzo quinone imine
bioactivation
Bioactivation of acetaminophen; under certain conditions, the electrophile N-acetyl
benzo quinone imine reacts with tissue macromolecules, causing liver necrosis

17. Some drugs that produce active or toxic
metabolite
Inactive drugs Active metabolite:
(Pro-drugs)
Cyclophophamide Phosphoramide musrard
Prednisone prednisolone
Active drug Active metabolite
Amitriptyline Nortriptyline
Diazepam Oxazepam
Active drug Toxic metabolite
Halothane Trifluoroacetic acid
Paracetamol N-acetyl-p-benzo-quinone-imine

18. Thalidomide is a Teratogen
(teratogenesis)
THALIDOMIDE:
Fetal malformations in humans, monkeys, and rats occur due to
metabolism of the parent compound to a teratogen. This occurs very
early in gestation

20. Sites of drug metabolism
 Liver is the principal organ of drug metabolism
 Other sites are GI mucosa, lungs, skin and kidneys
 Every tissue has some ability to metabolize drugs
 Some drugs, after oral administration (clonazepam & propranolol) are
extensively metabolized in GI or liver,
before reaching systemic circulation or sit of action,
called 1st pass effect, it reduces their bioavailability
 In the liver cells metabolic enzymes are located in the smooth microsomes
of endoplasmic reticulum

21. CELLULAR SITES OF DRUG
METABOLISM
Cytosol
 Mitochondria
Lysosomes
Smooth endoplasmic reticulum (microsomes)

22. Phases of drug metabolism

23. Phases of drug metabolism(cont…)
Drug metabolism can be categorized to:
Phase-I reactions: oxidations, reductions & hydrolysis
Phase-II reactions: conjugations
Glucuronide conjugation
Aspirin Salicylic acid
COOH COOH
COOH
OCOCH3
OH OH
O OH
HO
Phase-I
Phase-II O
COOH

24. DRUG METABOLISING ENZYMES
Microsomal enzymes
Non microsomal enzymes

25. METHODS FOR THE STUDY OF DRUG METABOLISM
1.
2.

26. METhODS USED In STUDy OF
METABOLISM

28. FACTORS AFFECTING DRUG METABOLISM

29. physico chemical properteis of
drug:

30. chemical factors:

31. ENZYME INDUCTION8
ENZYME INDUCTION 8
• Enzyme Induction - increased enzyme protein levels in the
cell
•Phenobarbital type induction by many drugs
•Polycyclic hydrocarbon type induction by polycyclic
hydrocarbons such as 3,4-benzopyrene and 3-
methylcholanthrene

33. CORRELATION BETWEEN SLEEPING TIME AND PLASMA
T1/2 IN CHRONIC PENTOBARBITAL PRETREATED RABBITS

34. Consequences of Induction
Increased rate of metabolism
Decrease in drug plasma concentration
Enhanced oral first pass metabolism
Reduced bioavailability
If metabolite is active or reactive, increased
drug effects or toxicity

35. Therapeutic Implications of Induction
Most drugs can exhibit decreased efficacy due to rapid metabolism
 but drugs with active metabolites can display
increased drug effect and/or toxicity due to enzyme
induction
Dosing rates may need to be increased to maintain
effective plasma concentrations

36. Enzyme inhibition
Product
metabolism Repression

37. Consequences of
Inhibition
Increase in the plasma concentration of parent drug
Reduction in metabolite concentration
Exaggerated and prolonged pharmacological effects
Increased liklihood of drug-induced toxicity

38. Therapeutic implications
of Inhibition
May occur rapidly with no warning
Particularly effects drug prescribing for patients on multidrug regimens
Knowledge of the CYP450 metabolic pathway provides basis for
predicting and understanding inhibition
Esp drug drug interaction

39. Enzyme inhibitors &drugs affected by them
Inhibitor Drugs affected
MAO Barbiturates,Tyramine
Coumarins Phenytoin
Allopurinol 6-mercaptopurin
PAS Phenytoin
Hexobarbitol

40. ENVIRONMENTAL CHEMICALS
DDT
Polycyclic aromatic hydrocarbons-enzyme induction effect
Organo phosphate insecticides
Heavy metals-Mercury,Cobalt,Arsenic(enzyme inhibition
effect)
Temperature
Atmospheric pressure

41. SPECIES VARIATION

42. Ethnic variations in the N-Acetylation of
Isoniazid
Ethnic group % of slow % of rapid
acetylators acetylators
Whiters 45 55
(USA,Canada)
Blacks(USA) 48 52
Latin Americans 67 33
American Indians 79 21
Japanes 87 13
Eskimos 98 05

43. AGE
Neonates
Children
Elderly

44. DIET
Charcoal broiled foods (contain polycyclic
hydrocarbons that increase certain enzyme protein in
cells)
Grapefruit juice (the active component is the
furancoumarin 6,7-dihydroxybergamottin which
inhibits a certain a group of microsomal enzymes)

45. State of health
 Hepatitis
 Liver cancer
 Cardiac insufficiency

46. CONCLUSION:
Final conclusion of this study is enzymes will play a major
role In drug metabolism especially cyp 450 .Lack of these
enzymes will sometimes makes the drug low efficient

47. CASE STUDY
A37-year-old woman visited her dentist for removal of her
wisdom teeth. The teeth were found to be impacted, and
removal necessitated extensive surgery. Following completion
of the procedure on one side of the mouth, the patient was given
a prescription for acetaminophen 300 mg with codeine 30 mg
(combination product) for the relief of pain. The patient took
the prescription as prescribed for approximately 2 days, but
little pain relief was achieved. She called the dentist to get a
prescription for another analgesic. What is a possible explanation
for this lack of efficacy?

49. REFERENCES
 SATYANARAYANA BIOCHEMISTRY
 J.L.JAIN FUNDAMENTALS OF BIOCHEMISTRY
 HERPER’S BIOCHEMISTRY
 MARTIN’S PHYSICAL PHARMACY
 INTERNET
 BRAHMANKER-BIOPHARMACEUTICS
 VENKATESHWARLU-BIOPHARMACEUTICS
 http://www.hospitalist.net/highligh.htm
 DR.A.V.S.S.RAMA RAO –A TEXT BOOK OF BIOCHEMISTRY
 LIPPINCOTT-MODERN PHARMACOLOGY WITH CLINICAL
APPLICATIONS
 GOODMAN GILMAN-PRINCIPLES OF PHARMACOLOGY