The document discusses drug metabolism and excretion. It describes how drugs are metabolized in two phases - phase I involves reactions like oxidation, reduction and hydrolysis that make the drug more polar. Phase II involves conjugating the drug or its metabolites to make them water soluble, such as by glucuronidation, sulfation or glutathione conjugation. The major site of drug metabolism is the liver, specifically the microsomal enzyme systems. Cytochrome P450 enzymes play a key role in phase I reactions like oxidation. Making drugs more polar allows them to be excreted in urine or bile.

1. DRUG DISPOSITION
AND EXCRETION
PRESENTED by
k.b.GAUThAmI
m-PhARmACy 1ST yEAR II SEm
(PhARmACEUTICS)
ROll NO: 256213886009.

3. bIOTRANSFORmATION
• Chemical alteration of a substance within the
body, as by the action of enzymes
• Vital to survival
• Key in defense mechanism….

4. METABOLISM OR BIOTRANSFORMATION
 The conversion from one chemical form of a substance to another.
 The term metabolism is commonly used probably because products of drug
transformation are called metabolites.
 Metabolism is an essential pharmacokinetic process, which renders lipid soluble and
non-polar compounds to water soluble and polar compounds so that they are
excreted by various processes.
 This is because only water-soluble substances undergo excretion, whereas lipid
soluble substances are passively reabsorbed from renal or extra renal excretory sites
into the blood by virtue of their lipophilicity.
 Metabolism is a necessary biological process that limits the life of a substance in the
body.
 Biotransformation: It is a specific term used for chemical transformation of
xenobiotics in the body/living organism.
• A series of enzyme-catalyzed processes—that alters the physiochemical properties
of foreign chemicals (drug/xenobiotics) from those that favor absorption across
biological membranes (lipophilicity) to those favoring elimination in urine or bile
(hydrophilicity )

5. Metabolism : It is a general term used for chemical
transformation of xenobiotics and endogenous
nutrients (e.g., proteins, carbohydrates and fats) within
or outside the body.
Xenobiotics : These are all chemical substances that
are not nutrient for body (foreign to body) and which
enter the body through ingestion, inhalation or dermal
exposure.
They include :
drugs, industrial chemicals, pesticides, pollutants,
plant and animal toxins, etc.

6. Site/Organs of drug metabolism
The major site of drug metabolism is the liver
(microsomal enzyme systems of hepatocytes)
Secondary organs of biotransformation
• kidney (proximal tubule)
• lungs (type II cells)
• testes (Sertoli cells)
• skin (epithelial cells); plasma. nervous tissue
(brain); intestines

7. Drug Metabolism
Extrahepatic microsomal enzymes
(oxidation, conjugation)
Hepatic microsomal enzymes
(oxidation, conjugation)
Hepatic non-microsomal enzymes
(acetylation, sulfation,GSH,
alcohol/aldehyde dehydrogenase,
hydrolysis, ox/red)

10. Uptake and excretion of hydrophilic and lipophilic compounds
UPTAKE
ORGAN
EXCRETION
UPTAKE
ORGAN
EXCRETION
UPTAKE
BIOTRANS-FORMATION
EXCRETION
Primarily biotransformation makes
lipophilic compounds more hydrophilic

11. REACTIONS
• PHASE I : modification
• PHASE II : conjugation

12. TYPES OF BIOTRANSFORMATION
Phase 1 reaction. (Non synthetic phase)
A change in drug molecule. generally
results in the introduction of a
functional group into molecules or the
exposure of new functional groups of
molecules
 : Phase I (non-synthetic or non-conjugative
phase) includes reactions
which catalyse oxidation, reduction
and hydrolysis of drugs.
 In phase I reactions, small polar
functional groups like-OH, -NH2. -SH,
-COOH, etc. are either added or
unmasked (if already present) on the
lipid soluble drugs so that the resulting
products may undergo phase II
reactions.
• result in activation, change or
inactivation of drug.
Phase II reaction. (Synthetic phase)
• Last step in detoxification reactions
and almost always results in loss of
biological activity of a compound.
• May be preceded by one or more of
phase one reaction
• Involves conjugation of functional
groups of molecules with hydrophilic
endogenous substrates- formation of
conjugates - is formed with (an
endogenous substance such as
carbohydrates and amino acids. )with
drug or its metabolites formed in
phase 1 reaction.
Involve attachment of small polar
endogenous molecules like glucuronic
acid, sulphate, methyl, amino acids,
etc., to either unchanged drugs or
phase I products.
Products called as 'conjugates' are
water-soluble metabolites, which are
readily excreted from the body.

13. • Phase I metabolism is sometimes called a
“functionalization reaction,”
• Results in the introduction of new
hydrophilic functional groups to compounds.
• Function: introduction (or unveiling) of
functional group(s) such as –OH, –NH2, –SH,
–COOH into the compounds.
• Reaction types: oxidation, reduction, and
hydrolysis
• Enzymes:
• Oxygenases and oxidases: Cytochrome P450 (P450
or CYP), flavincontaining
• monooxygenase (FMO), peroxidase, monoamine
oxidase(MAO), alcohol dehydrogenase, aldehyde
dehydrogenase, and xanthine 0xidase. Reductase:
Aldo-keto reductase and quinone reductase.
• Hydrolytic enzymes: esterase, amidase, aldehyde
oxidase, and alkylhydrazine
• oxidase.
• Enzymes that scavenge reduced oxygen:
Superoxide dismutases, catalase,
• glutathione peroxidase, epoxide hydrolase, y-glutamyl
transferase,
• dipeptidase, and cysteine conjugate β-lyase
• Phase II metabolism includes what are
known as conjugation reactions.
• Generally, the conjugation reaction with
endogenous substrates occurs on the
metabolite( s) of the parent compound after
phase I metabolism; however, in some cases,
the parent compound itself can be subject to
phase II metabolism.
• Function: conjugation (or derivatization) of
functional groups of a compound or its
metabolite(s) with endogenous substrates.
• Reaction types: glucuronidation, sulfation,
glutathione-conjugation, Nacetylation,
methylation and conjugation with amino acids
(e.g., glycine, taurine, glutamic acid).
• Enzymes: Uridine diphosphate-Glucuronosyltransferase
(UDPGT): sulfotransferase (ST), N-acetyltransferase,
glutathione S-transferase (GST),methyl transferase, and
amino acid conjugating enzymes.
• Glucuronidation by uridine diphosphate-glucuronosyltransferase;
Sulfation by sulfotransferase
• 3. Acetylation by N-acetyltransferase; Glutathione
conjugation by glutathione S-transferase;. Methylation by
methyl transferase; Amino acid conjugation

15.  A small polar group is either exposed on
the toxicant or added to the toxicant…
 Oxidation
 Reduction
 Hydrolysis
 Acetylation

16. PHASE I REACTION
OXIDATION
 substrate loses electrons
 addition of oxygen, dehydrogenation, or
simply transfer of electrons…

17.  alcohol dehydrogenation
 aldehyde dehydrogenation
 alkyl/acyclic hydroxylation
 aromatic hydroxylation
 deamination
 desulfuration
 N-dealkylation
 N-hydroxylation
 N-oxidation
 O-dealkylation
 sulphoxidation

18. Aliphatic hydroxylation
Aromatic hydroxylation
R R OH
Epoxidation
O
R - CH CH - R’ R - CH - CH - R’
N-, O-, or S-dealkylation
H
R - (N, O, S) - CH3
Deamination
N - hydroxylation
O
R - C - H + NH3
O O
R - NH - C – CH 3 R - NOH - C – CH3
Sulphur oxidation
R - S - R’ R - S - R’
S
R1R2P - X R1R2P - X + S
X X O
R - C - H R - C - OH R - C - H + HX
H H
O
De-sulphurnation
Oxidative dehalogenation
R - CH2 – CH2 – CH3 R – CH2 – CHOH – CH3
R – (NH2, OH, SH) + CH2O
R – CH2 – NH2

19. PHASE I REACTION
REDUCTION
 Substrate gains electrons
 Occurs when oxygen content is low
 Common reaction
 azo reduction
 dehalogenation
 disulfide reduction
 nitro reduction
 N-oxide reduction
 sulfoxide reduction

21. PHASE I REACTION
HYDROLYSIS
 Addition of water splits the molecule into
two fragments or smaller molecules
 -OH gp to one fragment and –H to other
 Eg : Larger chemicals such as esters,
amines, hydrazines, and carbamates

23.  Conjugation
 Endogenous substance is added to the
reactive site of the Phase I metabolite
 more water-soluble

25. TYPE I
• Methylation
• Glucuronidation
• Sulfation
• Acetylation
TYPE II
• Peptide conjugation
• Glutathione conjugation
• Glycosylation

26.  glucuronide conjugation
 sulfate conjugation
 acetylation
 amino acid conjugation
 glutathione conjugation
 methylation

27. CCOOFFAACCTTOORRSS
TYPE 1- REacTIvE/ acTIvaTEd
cofacToR
a)UDP- Glucuronic acid
b)PAPS
c)Acetyl CoA
d)SAM

28. TYPE 2- REacTIvE XEnobIoTIc
a)Glutathione
b)Aminoacids(glycine,glutamine,
taurine)

29.  Glucuronosyltransferase
 Sulfotransferase
 Glutathione-S-transferase
 Acetyltransferase

30.  GLUCURONIDE CONJUGATION
 glucuronic acid from glucose
 Sites involve substrates having O2, N2 or S
bonds
 Includes xenobiotics as well as endogenous
substances
 Reduces toxicity..(sometimes produce
carcinogenic substances)
 Excreted: kidney or bile depending on
conjugate size

32. GLUcURonIdE conJUGaTIon
COOH
R – OH + O UDP
HO
O
OH
OH
COOH
Glucuronyl
transferase O
HO
O
OH
OH
R + UDP

33. SULPHATE CONJUGATION
 Decreases toxicity
 readily excreted by urine
 Sulphotransferase
 PAPS limits the pathway

34. SULFATE CONJUGATION

35. glucuronidation or sulfation can conjugate
the same xenobiotics
Primary, secondary, phenols, catechols, N-oxides,
amines undergo this…

36. GLUTATHIONE CONJUGATION
 Conjugate loses glutamic acid and glycine
 Cysteine is N-acetylated to give stable
mercapturic acid derivatives

37. N
O
H
O
H
N
N
+ H
S
H
O
N
O
O
H H
H O
H
+
O
O
O
H H
O
H
H
N
O
S
H H
O
H
H H
N
O
O
H
Glutamic
acid
Cysteine
Glycine Glutathione

40. ACETYLATION
 the water solubility of parent molecule
and their excretion
 Masks the functional group of parent
from participating in conjugations
 Acetyl transferases
 Aromatic amines or hydrazine group to
amides or hydrazides

41. Methylation
 Makes slightly less soluble
 Masks available functional groups
 Types
O- methylation
N- methylation
S- methylation

43. PHASE II REACTIONS
• Aminoacid conjugation

44. GENETICS
Nfr2- nuclear factor erythroid derived
Inactive oxidative stress active
CP nucleus

45. ENZYMES
ENZYMES
microsomal…. Phase I and glucuronidation enzymes
Cytosolic enzymes….phase II and oxidation and
reduction
Mitochondrial, nuclei and lysosomes contain a little
transforming activity….

46. MICROSOMAL
Phase I reactions
– Most oxidation and
reduction
– Some hydrolysis
Phase II reactions
– ONLY Glucuronide
conjugation
• Inducible
– Drugs, diet, etc.
• SER
NONMICROSOMAL
Phase I reactions
– Most hydrolysis
– Some oxidation and
reduction
Phase II reactions
ALL except Glucuronide
conjugation
• Not inducible
• CP, MT etc

47. ENZYMES
• High molecular weight proteins..

48. MONOOXYGENASES
CYTOCHROME P450 ENZYME SYSTEM
• Mixed function oxidase
• Commonly in microsomes
• Important in plant terpenoid biosynthesis
• In phase I reactions
• Contains 2 enz NADPH CYP reductase and
cyp 450

49. CYTOCHROME PP445500 EENNZZYYMMEE SSYYSSTTEEMM
 superfamily of heme-dependent proteins
expressed in mammals mainly in the liver,
with lower levels of expression in the
small intestine, lungs, kidneys, brain and
placenta
In man, to date 57 different P450
isoforms have been identified, which were
assigned to 18 families and 43 subfamilies
based on their protein sequences

50. REDUCTASE
P-450 P-450

51. TYPES
• Microsomal P450 systems: electrons are
transferred from NADPH via
cytochrome P450 reductase.
• Mitochondrial P450 systems: employ
adrenodoxin reductase and adrenodoxin to transfer
electrons from NADPH to P450.

52. CYTOCHROME P 450 ENZYME ACTION

53. HC
(inducer)
Ah receptor-hsp90
HC
Nucleus
P450 protein P450 mRNA
• Bioactivation
• Detoxification
Toxicity
Elimination
Cell
HC-AhR
hsp90
HC-AhR
XRE
P450 gen
HC: Hydrocarbon (inducer)
XRC: Regulator gene (stimulates
transcription of P-450 gene)

54. P450 family Function
CYP1, CYP2, CYP3 Metabolism of drugs and xenobiotics
CYP4, CYP5, CYP8
Fatty acids hydroxylation, biosynthesis of
prostaglandins, prostacyclins and thromboxanes
CYP7, CYP11, CYP17, CYP19
(=steroid aromatase), CYP21,
CYP24, CYP27, CYP39, CYP46,
CYP51 Biosynthesis and metabolism of cholesterol, steroid
hormones and bile acids
CYP26 Retinoic acid hydroxylation
CYP20 Unknown

55. FLAVIN MONO OXYGENASE
• Microsomal enzyme
• mixed function amine oxidase
• Cofactors: NADPH, molecular O₂
• Do not contain heme
• Broad specificity
• Nicotine detoxification

56. OTHER ENZYMES
•Monoamine oxidases- breakdown of
neurotransmitters and antidepressant
drugs
• Alcohol and aldehyde dehydrogenases

57. TYPES OF FACTORS
• Chemical
• Biological
• Altered Physiological
• Temporal
• Route of Drug Administration
• Enviornmental

58. Chemical Factors
1. Enzyme Induction
2. Enzyme Inhibition

59. Enzyme Induction
It is a process in which a drug induces or enhances
the expression of an enzyme.
Rifampicin If taken by female patients taking contraceptives,
causes decreased therapeutic effect, leading to pregnancy.
Phenobarbitone If administered to patients taking warfarin,
may cause therapeutic failure, leading to increased
bleeding tendency.
Auto induction: The phenomenon in which a
drug induces metabolism of other drugs as well
as its own E.g. carbamazepine-antiepileptic.

60. Enzyme Inhibition
Decrease in the drug metabolizing ability of
enzymes. Competition for the active sites
takes place between the inhibitor and the
drugs. When enzyme inhibitor attaches,
less metabolism occurs. E.g.
 Sulfonamides decrease the metabolism of phenytoin so
that its blood levels become toxic.
 Cimetidine decreases the metabolism of propanolol
leading to enhanced bradycardia.
 Oral contraceptives inhibit metabolism of antipyrine.

61. Biological Factors
AGE
In infants microsomal enzyme system is not
fully developed. The rate of metabolism is
very low. Care should be taken in
administering drugs in younger patients.
 Chloramphenicol does not have great
efficacy in infants. Toxic effects in the form of
grey baby syndrome might occur. The baby
may be cyanosed, hypothermic, flaccid and
grey in color. Shock and even death might
occur if toxic levels get accumulated.
 Diazepam may result in floppy baby
syndrome in which flaccidity of the baby is
seen.

62. AGE
In elderly, most processes slow down
which leads to decreased
metabolism. Shrinkage of organs
occurs as well along with
decreased liver functions and
decreased blood flow through the
liver. All these factors decrease the
metabolism.
The drug doses should be decreased
in the elderly

63. GENDER
Gender related differences in the rate of
metabolism are attributed to sex hormones
and are generally observed following
puberty.
 Male have a higher BMR as compared to the
females, thus can metabolize drugs more
efficiently, e.g. salicylates and others might
include ethanol, propanolol,
benzodiazepines.
 Women on oral contraceptives metabolize
drugs at a slower rate

64. GENETICS
Drugs behave differently in different individuals due to
genetic variations
Succinyl choline, which is a skeletal muscle relaxant, is metabolized
by pseudocholine esterase. Some people lack this enzyme, due to
which lack of metabolism of succinyl choline might occur. When
administered in those individuals, prolonged Apnea might result.
Different groups of populations might be classified as fast
metabolizers and poor metabolizers of drugs.
For drugs, like Isoniazid, fast acetylators as well as slow acetylators
are present. Fast acetylators cause rapid acetylation, while poor
metabolizers metabolize less. Hepatic acetyl transferrase catalyzes
acetylation. Slow acetylation might occur due to genetic
malformation leading to decreased production.

65. RACE/SPECIES
 Asians, Orientals, Blacks and
Whites might have different drug
metabolizing capacity. Examples
include difference in drug
metabolizing capacity of certain anti
malarial.
 Eskimos metabolize drugs faster
than Asians.
 Laboratory animals can metabolize
drugs faster than man e.g.
barbiturates.

66. DIET
The enzyme content and activity is
altered by a number of dietary
components.
 Low protein diet decreases and high
protein content in diet increases the
drug metabolizing ability.
 Dietary deficiency of vitamins and
minerals retard the metabolic activity
of enzymes.

67. ALTERED PHYSIOLOGICAL
FACTORS
PREGNANCY
During pregnancy, metabolism of some
drugs is increased while that of others
is decreased due to the presence of
steroid hormones e.g.
 Phenytoin
 Phenobarbitone
 Pethidine

68. HORMONAL IMBALANCE
Higher levels of one hormone may inhibit the
activity of few enzymes while inducing that of
others. E.g.
 Hypothyroidism increases drug metabolizing
capacity (increased half life of antipyrine,
digoxin, methimazole, practolol) while
hyperthyroidism decreases it.

69. DISEASE STATES
Liver disease such as hepatic carcinoma, cirrhosis,
hepatitis, obstructive jaundice etc reduce the
hepatic drug metabolizing ability and thus increase
the half lives of almost all drugs.
In renal diseases conjugation of salycylates,
oxidation of vitamin D and hydrolysis of Procaine
are impaired.
Cardiovascular diseases, although have no direct
effect, decrease the blood flow, which may slow
down biotransformation of drugs like isoniazid,
morphine and propanolol.
Pulmonary conditions may
decrease biotransformation. Procaine and
procainamide hydrolysis is impaired.

70. TEMPORAL FACTOR
Diurnal variations and variations in enzyme
activity with light cycle is circadian rhythm.
Enzyme action is maximum during early
morning and minimum in late afternoon which
is probably due to high levels of
coticosterone.

71. ROUTE OF ADMINISTRATION
Oral route can result in extensive hepatic metabolism of
some drugs (first pass effect).
Lignocaine is almost completely metabolized if taken by
oral route therefore the preferable route is Topical.

72. ENVIRONMENTAL FACTORS
 Aromatic hydrocarbon contained in Cigarette
smokers act as enzyme inducers.
 Chronic alcoholism might lead to enzyme
induction as well.
 Pesticides or Organophosphate insecticides
may act as enzyme inducers.
 In hot and humid climate biotransformation is
decreased and vice versa.
 At high altitude
decreased biotransformation occurs due to
decreased oxygen leading to decreased
oxidation of drugs.

73. REFERENCE
• http://www.eoearth.org/article/Biotransformation?topic=58074
• profiles.nlm.nih.gov/ps/access/CCAAOR.pdf
• www.slideshare.net/shishirkawde/biotransformation-10417087
• www.eolss.net/sample-chapters/c17/e6-58-04-06.pdf
• www.ncbi.nlm.nih.gov/pubmed/3116933
• ingentaconnect.com RK Venisetty, V Ciddi - Current pharmaceutical
biotechnology, 2003
• web.squ.edu.om/med-Lib/MED_CD/E_CDs/.../020160r00.HTM
• www.eoearth.org/article/Biotransformation