DRUG METABOLISM

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INDIAN DENTAL ACADEMY
Leader in continuing dental education
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Transformation of Xenobiotics by Biological Systems

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IMPLICATIONS FOR DRUG METABOLISM

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IMPLICATIONS FOR DRUG METABOLISM

1.

Termination of drug action

2.

Activation of prodrug

3.

Bioactivation and toxicat...
Termination of Drug Action

atropine

propranolol
(active)

tropic acid and tropine

→

hydroxypropranolol
(active)
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Termination of Drug Action

Conversion of drug to active metabolite to active
metabolite to inactive metabolite

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Activation of Prodrug

L-dopa

Dopamine

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Inactive Terfenadine is Converted to its Active
Metabolite Fexofenadine
activation of prodrug

terfenadine

fexofenadine

...
Some Xenobiotics Are Metabolized to Carcinogenic Agents
carcinogenesis

• 3,4 Benzopyrene
• Aflatoxin
• N-Acetylaminoflluo...
Small Amounts of Acetaminophen is Converted to the
Reactive Metabolite N-Acetylbenzoquinoneimine
bioactivation

Bioactivat...
Thalidomide is a Teratogen
teratogensis

– THALIDOMIDE: Fetal malformations in
humans, monkeys, and rats occur due to
meta...
FACTORS AFFECTING DRUG METABOLISM

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Factors Affecting Drug Metabolism
•
•
•
•
•
•
•
•
•
•

Age
Diet
Genetic Variation
State of Health
Gender
Degree of Protein...
Factors Affecting Drug Metabolism

• Route of drug administration
– Oral versus systemic administration

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Many Drugs Undergo First Pass Metabolism
Upon Oral Administration
• Oral administration
• Drug travels from gut to portal ...
ORGAN SITES OF DRUG METABOLISM

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Organ Sites of Drug Metabolism

•
•
•
•
•
•
•

Liver
Small intestine
Kidney
Skin
Lungs
Plasma
All organs of the body

www....
CELLULAR SITES OF DRUG
METABOLISM

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Cellular Sites Of Drug Metabolism

•
•
•
•

Cytosol
Mitochondria
Lysosomes
Smooth endoplasmic reticulum
(microsomes)

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KINETICS OF DRUG METABOLISM

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80

Velocity Of Metabolism Of A Drug

70

Velocity
(ng/g tissue/min)

60
50
40
30
20
10
0
0

10

20

30

40

[Drug] mM

ww...
Velocity Of Metabolism Of A Drug
80
70

Velocity
(ng/g tissue/min)

60

zero order metabolism

50
40
30
20
10
0
0

first o...
First Order Metabolism
A drug may be given in doses that produce blood
concentrations less than the Km of the enyzme for t...
Velocity Of Metabolism Of A Drug
80
70

Velocity
(ng/g tissue/min)

60

zero order metabolism

50
40
30
20
10
0
0

first o...
Zero Order Metabolism
A drug may be given in doses that produce blood concentrations
greater than the Km of the enyzme for...
Velocity Of Metabolism Of A Drug
80
70

Velocity
(ng/g tissue/min)

60

zero order metabolism

50
40
30
20
10
0
0

first o...
Velocity

(ng/g tissue/min )

Velocity Of Metabolism Of Three Drugs
By The Same Enzyme
70

60
50

Drug A
Drug B
Drug C

40...
PHASES OF DRUG METABOLISM

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Phase I Metabolism
Polar groups are exposed on or introduced to a molecule

R

ROH

R

R
COOH

R

RSH

R

RNH2

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Phase I Reactions

OXIDATION
REDUCTION
HYDROLYSIS

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Phase II Metabolism
A molecule endogenous to the body donates a portion
of itself to the foreign molecule

D+ENDOX

DX+END...
Patterns of Drug Metabolism
• Parent molecule → Phase 1 metabolism
• Phase 1 metabolite → Phase 2 metabolism
• Parent mole...
PHASE I METABOLIC PATHWAYS

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Microsomal Oxidation

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Preparation Of Microsomes

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Cytochrome P450

fp = NADPH cytochrome P450 reductase, or NADH cytochrome b5
reductase
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Oxidation Of Drugs By Cytochrome P450

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Oxidation Of Drugs By Cytochrome P450

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Aliphatic Oxidation

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Aromatic Hydroxylation (1)

acetanilid

p-hydroxyacetanilid

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Aromatic Hydroxylation (2)

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N-Dealkylation

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O-Dealkylation

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S-Demethylation

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Oxidative Deamination

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S-Oxidation

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N-Oxidation

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N-Hydroxylation

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N-Hydroxylation of AAF

N-Hydroxylation of AAF is the first metabolic step towards
the development of a carcinogenic agent...
Oxidative Dehalogenation

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Desulfuration

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Desulfuration

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ISOENZMYES OF CYTOCHROME P450
CYP1A1

CYP2D6

CYP1A2

CYP2AE1

CYP2A6

CYP3A4

CYP2B_

CYP3A5

CYP2C9

CYP3A7

CYP2C19

CY...
Cytochrome P450 3A4
(CYP3A4)

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CYP3A4
• CYP3A4 is responsible for metabolism of 60%
of all drugs
• It comprises approximately 28% of hepatic
cytochrome P...
Some Drugs That Inhibit CYP3A4
• Macrolide antibiotics
– Erythromycin
– Clarithromycin
– Other such agents

• Antifungal a...
CYP3A4

• Ketoconazole and terfenadine can produce a
drug interaction with fatal consequences.

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CONVERSION OF TERFENADINE TO FEXOFENADINE

O2, NADPH

CYP3A4

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AN INGREDIENT IN GRAPEFRUIT JUICE
INHIBITS CYP3A4

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Grapefruit Juice Increases Felodipine Oral Availability in
Humans by Decreasing Intestinal CYP3A Protein Expression

Hours...
6',7', - Dihydroxybergamottin

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Grapefruit Juice Consumption Blocks Terfenadine
Metabolism to Fexofenadine

X

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CYP3A4 And P-Glycoprotein
• P-Glycoprotein and CYP3A4 control oral bioavailability
of many drugs
• P-Glycoprotein and CYP3...
CYP2D6 is an Enzyme with Polymorphisms
• Approximately 70 nucleotide polymorphisms are
known
• Four phenotype subpopulatio...
Codeine is a Substrate of CYP2D6

-CH3

(methyl morphine)

Consider the variation in codeine’s metabolism among
PM, IM, EM...
CYP2C9
• Metabolizes some 16 commonly used drugs
• Warfarin and phenytoin are among the substrates
• Two allelic variants ...
CYP2C19
• S-mephenytoin is a substrate

– (4-hydroxylation at the phenyl ring)
• As much as eight allelic variants identif...
CYP1A1
• Polycyclic hydrocarbons are among its
substrates
• Inducers include
– Polycyclic hydrocarbons such as 3,4,-benzop...
CIMETIDINE Inhibits CYP450 Metabolism Of Many Drugs

Warfarin

Triazolam

Phenytoin

Chlordiazepoxide

Metoprolol

Carbama...
NONMICROSOMAL OXIDATIONS
ALCOHOL DEHYDROGENATION
ALDEHYDE DEHYDROGENATION
XANTHINE OXIDATION
DIAMINE OXIDATION
MONOAMINE O...
Nonmicrosomal Oxidations
Alcohol dehydrogenation is conducted by the enzyme
alcohol dehydrogenase (cytosolic)
Aldehyde deh...
Monoamine Oxidase Metabolism of Serotonin

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Some Popular Substrates of Monoamine Oxidase

•
•
•
•
•

Serotonin
Epinephrine
Norepinephrine
Dopamine
Tyramine (found in ...
Diamine Oxidase

cadaverine

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Alcohol Dehydrogenase

• A soluble enzyme, found almost exclusively in the
parenchymal cells of the liver
• Converts ethan...
Alcohol Dehydrogenase

CH3CH2OH + NAD+ → CH3CHO + NADH + H+
ethanol

acetaldehyde

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Aldehyde Dehydrogenase

CH3CHO + NAD+ → CH3COOH + NADH + H+
acetaldehyde

acetate

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XANTHINE OXIDASE

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Xanthine Oxidase

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REDUCTION

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Nitro Reduction
NITRO REDUCTION

RNO2

RNH2

MICROSOMES AND CYTOSOL
Microsomes and cytosol

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Nitro Reduction

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Azo Reduction

AZO REDUCTION
RN=NR'

RNH2 + R'NH2

Microsomes and cytosol

MICROSOMES AND CYTOSOL
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Azo Reduction

Microsomes and cytosol

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Alcohol Dehydrogenation

Cytosol

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DIHYDROPYRIMIDINE DEHYDROGENASE

5-Fluorouracil

DPYD

5-Fluoro-5,6-dihydrouracil

• DPYD
– Inactivates 5-fluorouracil by ...
HYDROLYSIS

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Amide Hydrolysis

AMIDE HYDROLYSIS
RCONR'R"

RCOOH+ HNR'R"

Microsomes and cytosol

MICROSOMES AND CYTOSOL

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Ester Hydrolysis
ESTER HYDROLYSIS

RCOOR'

RCOOH + R'OH

MICROSOMES AND CYTOSOL

Microsomes and cytosol

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Ester Hydrolysis

Enalaprit

Microsomes and cytosol

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EPOXIDE HYDROLASE

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Epoxide Hydrolase
• A microsomal enzyme

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Epoxide Hydrolase

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PHASE II METABOLIC PATHWAYS

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PHASE 2 METABOLISM

A molecule endogenous to the body donates a portion
of itself to the foreign molecule

D+ENDOX

DX+END...
PHASE II REACTIONS
Glucuronidation
Sulfate Conjugation
Acetylation
Glycine Conjugation
Methylation
Transulfuration
Glutath...
GLUCURONIDATION

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Uridine-5’-α-D-glucuronic Acid

The microsomal enzyme glucuronyl transferase conducts the
donation of glucuronic acid from...
UDP-α-D-Glucuronsyltransferase
•
•
•
•
•

Is also called glucuronyl transferase
A microsomal enzyme
Substrates are called ...
Glucuronidation of Benzoic Acid

UGT= UDP-α-D-Glucuronsyltransferase
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Glucuronidation of Aniline

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Glucuronidation of p-Hydroxyacetanilid

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Morphine Metabolism

→
Morphine →
Morphine

Morphine -6-glucuronide (active metabolite)
Morphine -3-glucuronide (inactive ...
Morphine Metabolism

Morphine -3-glucuronide is the major metabolite
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Induction Of UDP-α-D-Glucuronyl Transferase

• Induced by phenobarbital
• Induced by 3-methylcholanthrene

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Glucuronidation in the Cat

• The cat can glucuronidate bilirubin but cannot
glucuronidate phenolic compounds such as phen...
SULFATE CONJUGATION

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Sulfate Conjugation
• Conducted by the soluble enzyme sulfotransferase
• Endogenous donor molecule to conjugation is
3’-ph...
3’-Phosphoadenosine-5’-phosphosulfate (PAPS)

The cytosolic enzyme sulfotransferase conducts the donation of
sulfate from ...
Sulfate Conjugation of p-Hydroxyacetanilid

PAP: 3’-phosphoadenosine- 5’-phosphate
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MINOXIDIL METABOLISM

MINOXIDIL

MINOXIDIL N-O-SULFATE

(inactive)

(active metabolite)

MINOXIDIL N-O-GLUCURONIDE
(inacti...
Species Differences in Sulfate Conjugation
• Some species are deficient in the sulfate conjugation
pathway
– Pig
– Opposum...
N-ACETYLATION

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N-Acetyltransferase
• A soluble enzyme
• Isoniazid is a substrate
• Genetic variation occurs

– Some individuals are fast ...
Acetyl CoA

Various acetylases, for examples, choline acetylase and N-acetyl
transferase, all soluble enzymes, conduct the...
N-Acetyltransferase

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N-Acetyltransferase
• The dog cannot acetylate aromatic amino
compounds because it lacks the appropriate
isoenzyme of NAT
...
SUGAR CONJUGATION

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Conversion of 6-Mercaptopurine to a Nucleotide

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METHYLATION

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S-Adenosylmethionine

Cytosolic enzymes such as catechol-O-methyl transferase (COMT) and
phenylethanolamine-N-methyl trans...
Methyltransferases
• A family of soluble enzymes that conducts

–
–
–

N-methylation; N-CH3
O-methylation; O-CH3
S-methyla...
N-Methyltransferases
PNMT- Phenylethanolamine-N-methyltransferase
Norepinephrine

PNMT
SAM

Epinephrine

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O-Methylation Of Catecholamines

COMT- catechol-O-methyltransferase

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O-Methylation of Norepinephrine
COMT- catechol-O-methyltransferase

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S-Methylation of 6-Mercaptopurine

TPMT - thiopurinemethyltransferase; some individuals are
deficient in this enzyme that ...
METABOLISM OF MERCAPTOPURINE (1)
6-Mercaptopurine

TMPT

6-Methylmercaptopurine

• TMPT -Thiomethylpurinetransferase
– Con...
AMINO ACID CONJUGATION

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AMINO ACID CONJUGATION

(mitochondria)
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Multiple Metabolic Pathways Exist
for Aspirin’s Metabolism

Hydolysis of aspirin produces salicyclic acid, as
seen in the ...
Salicyluric Acid is the Glycine Conjugate of Aspirin

Salicyluric acid, the glycine conjugate of salicyclic acid, is the m...
Acetyl Salicylic Acid (Aspirin) Metabolism
• Salicylic acid the hydrolytic product of acetyl salicylic
acid. Salicylic aci...
TRANSULFURATION

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TRANSULFURATION

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GLUTATHIONE CONJUGATION

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DRUG INTERACTION WITH GLUTATHIONE

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mercapturate
metabolite of drug
MERCAPTURIC ACID FORMATION
• Conjugation of substrate to glutathione by the
enzyme glutathione transferase
• Hydrolytic re...
ACETAMINOPHEN METABOLISM

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Bioactivation of Acetaminophen

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ACETAMINOPHEN AND ITS PHASE II METABOLITES

The sulfate and glucuronide conjugates of acetaminophen are the major
metaboli...
ACETAMINOPHEN AND ITS PHASE I METABOLITES

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ACETAMINOPHEN AND ITS PHASE I METABOLITES- pt2

The minor metabolite (4% of acetaminophen), N-hydroxyacetaminophen,
is alw...
N-ACETYLCYSTEINE FOR ACETAMINOPHEN TOXICITY

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CARCENOGENSIS

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N-Hydroxylation of AAF

N-Hydroxylation of AAF is the first metabolic step towards
the development of a carcinogenic agent...
Further Metabolism of N-HydroxyAAF Produces Cancer

N-HydroxyAAF undergoes phase II metabolism to the
ultimate carcingogen...
CYP1A1 Converts Benzopyrene to a Carcinogen

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Aflatoxin is Metabolized to a Carcinogenic Agent

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FACTORS AFFECTING DRUG METABOLISM

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ENZYME INDUCTION

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

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Factors Affecting Drug Metabolism
• Enzyme Induction - increased enzyme protein levels
in the cell
– Phenobarbital type in...
AGE

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FACTORS AFFECTING DRUG METABOLISM

• Age
– Neonates
– Children
– Elderly

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DIET

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FACTORS AFFECTING DRUG METABOLISM
• Diet
– Charcoal broiled foods (contain polycyclic
hydrocarbons that increase certain e...
GENETIC VARIATION

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Some Enzymes That Exhibit Genetic Variation
– Pseudocholinesterase
• typical enzyme
• atypical enzyme
– N-Acetyltransferas...
STATE OF HEALTH

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FACTORS AFFECTING DRUG METABOLISM

• State of health
– Hepatitis
– Liver cancer
– Cardiac insufficiency
– Uremia
• degree ...
Changes In Drug Metabolism As A Consequence Of Hepatic Disease

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From Principles of Drug Action
GENDER

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FACTORS AFFECTING DRUG METABOLISM
• Gender
– Most studies are performed in the rat. In general,
male rats metabolize drugs...
DEGREE OF PROTEIN BINDING

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FACTORS AFFECTING DRUG METABOLISM

• Degree of protein binding
– Conditions that displace bound drug from protein
allows m...
SPECIES VARIATION

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FACTORS AFFECTING DRUG METABOLISM

• Species variation
– Quantitative
– Qualitative

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Factors Affecting Drug Metabolism

• Species variation
– Human beings metabolize amphetamine by
deamination; rats and dogs...
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SUBSTRATE COMPETITION

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Factors Affecting Drug Metabolism

• Substrate competition
– Two or more drugs competing for the same
enzyme can affect th...
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Leader in continuing dental education

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Drug metabolism /certified fixed orthodontic courses by Indian dental academy

  1. 1. DRUG METABOLISM www.indiandentalacademy.com
  2. 2. INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com www.indiandentalacademy.com
  3. 3. Transformation of Xenobiotics by Biological Systems www.indiandentalacademy.com
  4. 4. IMPLICATIONS FOR DRUG METABOLISM www.indiandentalacademy.com
  5. 5. IMPLICATIONS FOR DRUG METABOLISM 1. Termination of drug action 2. Activation of prodrug 3. Bioactivation and toxication 4. Carcinogenesis 5. Tetratogenesis www.indiandentalacademy.com
  6. 6. Termination of Drug Action atropine propranolol (active) tropic acid and tropine → hydroxypropranolol (active) www.indiandentalacademy.com
  7. 7. Termination of Drug Action Conversion of drug to active metabolite to active metabolite to inactive metabolite www.indiandentalacademy.com
  8. 8. Activation of Prodrug L-dopa Dopamine www.indiandentalacademy.com
  9. 9. Inactive Terfenadine is Converted to its Active Metabolite Fexofenadine activation of prodrug terfenadine fexofenadine www.indiandentalacademy.com
  10. 10. Some Xenobiotics Are Metabolized to Carcinogenic Agents carcinogenesis • 3,4 Benzopyrene • Aflatoxin • N-Acetylaminoflluorene Metabolites of these agents interact with DNA www.indiandentalacademy.com
  11. 11. Small Amounts of Acetaminophen is Converted to the Reactive Metabolite N-Acetylbenzoquinoneimine bioactivation Bioactivation of acetaminophen; under certain conditions, the electrophile Nacetylbenzoquinoneimine reacts with tissue macromolecules, causing liver necrosis. www.indiandentalacademy.com
  12. 12. Thalidomide is a Teratogen teratogensis – 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. www.indiandentalacademy.com
  13. 13. FACTORS AFFECTING DRUG METABOLISM www.indiandentalacademy.com
  14. 14. Factors Affecting Drug Metabolism • • • • • • • • • • Age Diet Genetic Variation State of Health Gender Degree of Protein Binding Species Variation Substrate Competition Enzyme Induction Route of Drug Administration www.indiandentalacademy.com
  15. 15. Factors Affecting Drug Metabolism • Route of drug administration – Oral versus systemic administration www.indiandentalacademy.com
  16. 16. Many Drugs Undergo First Pass Metabolism Upon Oral Administration • Oral administration • Drug travels from gut to portal vein to liver • Vigorous metabolism occurs in the liver. Little drug gets to the systemic circulation • The wall of the small intestine also contributes to first pass metabolism www.indiandentalacademy.com
  17. 17. ORGAN SITES OF DRUG METABOLISM www.indiandentalacademy.com
  18. 18. Organ Sites of Drug Metabolism • • • • • • • Liver Small intestine Kidney Skin Lungs Plasma All organs of the body www.indiandentalacademy.com
  19. 19. CELLULAR SITES OF DRUG METABOLISM www.indiandentalacademy.com
  20. 20. Cellular Sites Of Drug Metabolism • • • • Cytosol Mitochondria Lysosomes Smooth endoplasmic reticulum (microsomes) www.indiandentalacademy.com
  21. 21. KINETICS OF DRUG METABOLISM www.indiandentalacademy.com
  22. 22. 80 Velocity Of Metabolism Of A Drug 70 Velocity (ng/g tissue/min) 60 50 40 30 20 10 0 0 10 20 30 40 [Drug] mM www.indiandentalacademy.com 50 60 70 D:summer1Kmx1.pzm
  23. 23. Velocity Of Metabolism Of A Drug 80 70 Velocity (ng/g tissue/min) 60 zero order metabolism 50 40 30 20 10 0 0 first order metabolism 5 10 15 20 25 30 35 40 45 50 55 60 [Drug] mM www.indiandentalacademy.com Kmx2.pzm
  24. 24. First Order Metabolism A drug may be given in doses that produce blood concentrations less than the Km of the enyzme for the drug. v = Vmax [C] Km + [C] When then Km >>> [C], v = Vmax [C] , Km and v α [C] Metabolism of the drug is a first order process. A constant fraction of the remaining drug is metabolized per unit time. Most drugs are given at concentrations smaller than the Km of the enzymes of their metabolism. www.indiandentalacademy.com
  25. 25. Velocity Of Metabolism Of A Drug 80 70 Velocity (ng/g tissue/min) 60 zero order metabolism 50 40 30 20 10 0 0 first order metabolism 5 10 15 20 25 30 35 40 45 50 55 60 [Drug] mM www.indiandentalacademy.com Kmx2.pzm
  26. 26. Zero Order Metabolism A drug may be given in doses that produce blood concentrations greater than the Km of the enyzme for the drug. v = Vmax [C] K m + [C] When [C] >>> Km, then v = Vmax [C] , [C] and v = Vmax Metabolism of the drug is a zero order process. A constant amount of the remaining drug is metabolized per unit time. Phenytoin undergoes zero order metabolism at the doses given. www.indiandentalacademy.com
  27. 27. Velocity Of Metabolism Of A Drug 80 70 Velocity (ng/g tissue/min) 60 zero order metabolism 50 40 30 20 10 0 0 first order metabolism 5 10 15 20 25 30 35 40 45 50 55 60 [Drug] mM www.indiandentalacademy.com Kmx2.pzm
  28. 28. Velocity (ng/g tissue/min ) Velocity Of Metabolism Of Three Drugs By The Same Enzyme 70 60 50 Drug A Drug B Drug C 40 30 20 10 0 0 10 20 30 40 50 [Drug] mM www.indiandentalacademy.com 60 70 80 90
  29. 29. PHASES OF DRUG METABOLISM www.indiandentalacademy.com
  30. 30. Phase I Metabolism Polar groups are exposed on or introduced to a molecule R ROH R R COOH R RSH R RNH2 www.indiandentalacademy.com
  31. 31. Phase I Reactions OXIDATION REDUCTION HYDROLYSIS www.indiandentalacademy.com
  32. 32. Phase II Metabolism A molecule endogenous to the body donates a portion of itself to the foreign molecule D+ENDOX DX+ENDO www.indiandentalacademy.com
  33. 33. Patterns of Drug Metabolism • Parent molecule → Phase 1 metabolism • Phase 1 metabolite → Phase 2 metabolism • Parent molecule → Phase 2 metabolism • Phase 2 metabolite → Phase 1 metabolism Some drugs are not metabolized, for example, gallamine and decamethonium. Atracurium undergoes spontaneous hydrolysis. www.indiandentalacademy.com
  34. 34. PHASE I METABOLIC PATHWAYS www.indiandentalacademy.com
  35. 35. Microsomal Oxidation www.indiandentalacademy.com
  36. 36. Preparation Of Microsomes www.indiandentalacademy.com
  37. 37. Cytochrome P450 fp = NADPH cytochrome P450 reductase, or NADH cytochrome b5 reductase www.indiandentalacademy.com
  38. 38. Oxidation Of Drugs By Cytochrome P450 www.indiandentalacademy.com
  39. 39. Oxidation Of Drugs By Cytochrome P450 www.indiandentalacademy.com
  40. 40. Aliphatic Oxidation www.indiandentalacademy.com
  41. 41. Aromatic Hydroxylation (1) acetanilid p-hydroxyacetanilid www.indiandentalacademy.com
  42. 42. Aromatic Hydroxylation (2) www.indiandentalacademy.com
  43. 43. N-Dealkylation www.indiandentalacademy.com
  44. 44. O-Dealkylation www.indiandentalacademy.com
  45. 45. S-Demethylation www.indiandentalacademy.com
  46. 46. Oxidative Deamination www.indiandentalacademy.com
  47. 47. S-Oxidation www.indiandentalacademy.com
  48. 48. N-Oxidation www.indiandentalacademy.com
  49. 49. N-Hydroxylation www.indiandentalacademy.com
  50. 50. N-Hydroxylation of AAF N-Hydroxylation of AAF is the first metabolic step towards the development of a carcinogenic agent www.indiandentalacademy.com
  51. 51. Oxidative Dehalogenation www.indiandentalacademy.com
  52. 52. Desulfuration www.indiandentalacademy.com
  53. 53. Desulfuration www.indiandentalacademy.com
  54. 54. ISOENZMYES OF CYTOCHROME P450 CYP1A1 CYP2D6 CYP1A2 CYP2AE1 CYP2A6 CYP3A4 CYP2B_ CYP3A5 CYP2C9 CYP3A7 CYP2C19 CYP4A_ www.indiandentalacademy.com
  55. 55. Cytochrome P450 3A4 (CYP3A4) www.indiandentalacademy.com
  56. 56. CYP3A4 • CYP3A4 is responsible for metabolism of 60% of all drugs • It comprises approximately 28% of hepatic cytochrome P450 • Metabolizes terfenadine • Ingestion of grapefruit juice reduces expression of this enzyme • Inhibited by some regularly used drugs www.indiandentalacademy.com
  57. 57. Some Drugs That Inhibit CYP3A4 • Macrolide antibiotics – Erythromycin – Clarithromycin – Other such agents • Antifungal agents – Ketoconazole – Itraconazole – Other such agents • HIV protease inhibitors www.indiandentalacademy.com
  58. 58. CYP3A4 • Ketoconazole and terfenadine can produce a drug interaction with fatal consequences. www.indiandentalacademy.com
  59. 59. CONVERSION OF TERFENADINE TO FEXOFENADINE O2, NADPH CYP3A4 www.indiandentalacademy.com
  60. 60. AN INGREDIENT IN GRAPEFRUIT JUICE INHIBITS CYP3A4 www.indiandentalacademy.com
  61. 61. Grapefruit Juice Increases Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression Hours www.indiandentalacademy.com J.Clin. Invest. 99:10, p.2545-53, 1997
  62. 62. 6',7', - Dihydroxybergamottin www.indiandentalacademy.com
  63. 63. Grapefruit Juice Consumption Blocks Terfenadine Metabolism to Fexofenadine X www.indiandentalacademy.com
  64. 64. CYP3A4 And P-Glycoprotein • P-Glycoprotein and CYP3A4 control oral bioavailability of many drugs • P-Glycoprotein and CYP3A4 share many substrates and inhibitors www.indiandentalacademy.com
  65. 65. CYP2D6 is an Enzyme with Polymorphisms • Approximately 70 nucleotide polymorphisms are known • Four phenotype subpopulations of metabolizers* – Poor metabolizers (PM) – Intermediate metabolizers (IM) – Extensive metabolizers (EM) – Ultrarapid metabolizers (UM) • Variations according to racial background • More than 65 commonly used drugs are substrates • Codeine is a well known substrate www.indiandentalacademy.com * The Pharmacological Basis of Therapeutics
  66. 66. Codeine is a Substrate of CYP2D6 -CH3 (methyl morphine) Consider the variation in codeine’s metabolism among PM, IM, EM, UM individuals www.indiandentalacademy.com
  67. 67. CYP2C9 • Metabolizes some 16 commonly used drugs • Warfarin and phenytoin are among the substrates • Two allelic variants are known: metabolizes substrates 5% to 12% of the wild type enzyme – Warfarin clearance is greatly reduced in individuals possessing the allelic variants • Dose adjustments are required for drugs in individuals who have the mutant enzymes www.indiandentalacademy.com
  68. 68. CYP2C19 • S-mephenytoin is a substrate – (4-hydroxylation at the phenyl ring) • As much as eight allelic variants identified – All are nonfunctional proteins • Poor metabolizers of S-mephenytoin lack 4-hydroxylase activity, but N-demethylation to nirvanol is an alternative but slow metabolic pathway – Dose adjustments must be made for poor metabolizers of S-mephenytoin and for other drugs that are substrates for this enzyme www.indiandentalacademy.com
  69. 69. CYP1A1 • Polycyclic hydrocarbons are among its substrates • Inducers include – Polycyclic hydrocarbons such as 3,4,-benzopyrene, 3-methylcholanthrene, etc. – Charcoal broiled foods (polycyclic hydrocarbons) www.indiandentalacademy.com
  70. 70. CIMETIDINE Inhibits CYP450 Metabolism Of Many Drugs Warfarin Triazolam Phenytoin Chlordiazepoxide Metoprolol Carbamazepine Labetalol Quinidine Quinidine Ethanol Caffeine Tricyclic antidepressants Lidocaine Theophylline Metronidazole Alprazolam Calcium channel blockers Diazepam Diazepam Flurazepam www.indiandentalacademy.com Sulfonylureas
  71. 71. NONMICROSOMAL OXIDATIONS ALCOHOL DEHYDROGENATION ALDEHYDE DEHYDROGENATION XANTHINE OXIDATION DIAMINE OXIDATION MONOAMINE OXIDATION www.indiandentalacademy.com
  72. 72. Nonmicrosomal Oxidations Alcohol dehydrogenation is conducted by the enzyme alcohol dehydrogenase (cytosolic) Aldehyde dehydrogenation is conducted by the enzyme aldehyde dehydrogenase (cytosol and mitochondria) Xanthine oxidation is conducted by the cytosolic enzyme xanthine oxidase. Diamine oxidase (cytosolic) oxidizes histamine and diamines such as cadaverine and putrescine. Monoamine oxidation is conducted by mitochondrial monoamine oxidase (norepinephrine, epinephrine, dopamine and serotonin are endogenous substrates. www.indiandentalacademy.com
  73. 73. Monoamine Oxidase Metabolism of Serotonin www.indiandentalacademy.com
  74. 74. Some Popular Substrates of Monoamine Oxidase • • • • • Serotonin Epinephrine Norepinephrine Dopamine Tyramine (found in certain foods) www.indiandentalacademy.com
  75. 75. Diamine Oxidase cadaverine www.indiandentalacademy.com
  76. 76. Alcohol Dehydrogenase • A soluble enzyme, found almost exclusively in the parenchymal cells of the liver • Converts ethanol to acetaldehyde • Converts methanol to formaldehyde • Converts ethylene glycol to its respective aldehyde metabolites • Is inhibited by pyrazole www.indiandentalacademy.com
  77. 77. Alcohol Dehydrogenase CH3CH2OH + NAD+ → CH3CHO + NADH + H+ ethanol acetaldehyde www.indiandentalacademy.com
  78. 78. Aldehyde Dehydrogenase CH3CHO + NAD+ → CH3COOH + NADH + H+ acetaldehyde acetate www.indiandentalacademy.com
  79. 79. XANTHINE OXIDASE www.indiandentalacademy.com
  80. 80. Xanthine Oxidase www.indiandentalacademy.com
  81. 81. REDUCTION www.indiandentalacademy.com
  82. 82. Nitro Reduction NITRO REDUCTION RNO2 RNH2 MICROSOMES AND CYTOSOL Microsomes and cytosol www.indiandentalacademy.com
  83. 83. Nitro Reduction www.indiandentalacademy.com
  84. 84. Azo Reduction AZO REDUCTION RN=NR' RNH2 + R'NH2 Microsomes and cytosol MICROSOMES AND CYTOSOL www.indiandentalacademy.com
  85. 85. Azo Reduction Microsomes and cytosol www.indiandentalacademy.com
  86. 86. Alcohol Dehydrogenation Cytosol www.indiandentalacademy.com
  87. 87. DIHYDROPYRIMIDINE DEHYDROGENASE 5-Fluorouracil DPYD 5-Fluoro-5,6-dihydrouracil • DPYD – Inactivates 5-fluorouracil by ring reduction – Inherited deficiency of this enzyme leads to 5-fluorouracil toxicity – Enzyme deficiency can be detected by enzymatic or molecular assays using white blood cells 5-fluorouracil www.indiandentalacademy.com
  88. 88. HYDROLYSIS www.indiandentalacademy.com
  89. 89. Amide Hydrolysis AMIDE HYDROLYSIS RCONR'R" RCOOH+ HNR'R" Microsomes and cytosol MICROSOMES AND CYTOSOL www.indiandentalacademy.com
  90. 90. Ester Hydrolysis ESTER HYDROLYSIS RCOOR' RCOOH + R'OH MICROSOMES AND CYTOSOL Microsomes and cytosol www.indiandentalacademy.com
  91. 91. Ester Hydrolysis Enalaprit Microsomes and cytosol www.indiandentalacademy.com
  92. 92. EPOXIDE HYDROLASE www.indiandentalacademy.com
  93. 93. Epoxide Hydrolase • A microsomal enzyme www.indiandentalacademy.com
  94. 94. Epoxide Hydrolase www.indiandentalacademy.com
  95. 95. www.indiandentalacademy.com
  96. 96. PHASE II METABOLIC PATHWAYS www.indiandentalacademy.com
  97. 97. PHASE 2 METABOLISM A molecule endogenous to the body donates a portion of itself to the foreign molecule D+ENDOX DX+ENDO www.indiandentalacademy.com
  98. 98. PHASE II REACTIONS Glucuronidation Sulfate Conjugation Acetylation Glycine Conjugation Methylation Transulfuration Glutathione Conjugation Mercapturic Acid Synthesis www.indiandentalacademy.com
  99. 99. GLUCURONIDATION www.indiandentalacademy.com
  100. 100. Uridine-5’-α-D-glucuronic Acid The microsomal enzyme glucuronyl transferase conducts the donation of glucuronic acid from the endogenously synthesized UDPGA to various substrates to form glucuronide conjugates. www.indiandentalacademy.com Examples of such substrates are morphine and acetaminophen.
  101. 101. UDP-α-D-Glucuronsyltransferase • • • • • Is also called glucuronyl transferase A microsomal enzyme Substrates are called aglycones Conducts phase 2 metabolic reactions Products are called glucuronides • Glucuronides formed – RN-G; RO-G; RCOO-G; RS-G; RC-G • Bilirubin is an endogenous substrate • Induced by phenobarbital www.indiandentalacademy.com
  102. 102. Glucuronidation of Benzoic Acid UGT= UDP-α-D-Glucuronsyltransferase www.indiandentalacademy.com
  103. 103. Glucuronidation of Aniline www.indiandentalacademy.com
  104. 104. Glucuronidation of p-Hydroxyacetanilid www.indiandentalacademy.com
  105. 105. Morphine Metabolism → Morphine → Morphine Morphine -6-glucuronide (active metabolite) Morphine -3-glucuronide (inactive metabolite) A small amount of morphine undergoes N-demethylation www.indiandentalacademy.com
  106. 106. Morphine Metabolism Morphine -3-glucuronide is the major metabolite www.indiandentalacademy.com
  107. 107. Induction Of UDP-α-D-Glucuronyl Transferase • Induced by phenobarbital • Induced by 3-methylcholanthrene www.indiandentalacademy.com
  108. 108. Glucuronidation in the Cat • The cat can glucuronidate bilirubin but cannot glucuronidate phenolic compounds such as phenol and napthol www.indiandentalacademy.com
  109. 109. SULFATE CONJUGATION www.indiandentalacademy.com
  110. 110. Sulfate Conjugation • Conducted by the soluble enzyme sulfotransferase • Endogenous donor molecule to conjugation is 3’-phosphoadenosine-5’-phosphosulfate (PAPS) • Conjugates are ethereal in character • Noninducible www.indiandentalacademy.com
  111. 111. 3’-Phosphoadenosine-5’-phosphosulfate (PAPS) The cytosolic enzyme sulfotransferase conducts the donation of sulfate from the endogenously synthesized PAPS to various substrates to form sulfate conjugates. An example of such substrate www.indiandentalacademy.com is acetaminophen.
  112. 112. Sulfate Conjugation of p-Hydroxyacetanilid PAP: 3’-phosphoadenosine- 5’-phosphate www.indiandentalacademy.com
  113. 113. MINOXIDIL METABOLISM MINOXIDIL MINOXIDIL N-O-SULFATE (inactive) (active metabolite) MINOXIDIL N-O-GLUCURONIDE (inactive metabolite) www.indiandentalacademy.com
  114. 114. Species Differences in Sulfate Conjugation • Some species are deficient in the sulfate conjugation pathway – Pig – Opposum www.indiandentalacademy.com
  115. 115. N-ACETYLATION www.indiandentalacademy.com
  116. 116. N-Acetyltransferase • A soluble enzyme • Isoniazid is a substrate • Genetic variation occurs – Some individuals are fast acetylators – Some individuals are slow acetylators • Acetyl coenzyme A is the endogenous donor molecule www.indiandentalacademy.com
  117. 117. Acetyl CoA Various acetylases, for examples, choline acetylase and N-acetyl transferase, all soluble enzymes, conduct the transfer of the acetyl group of acetyl CoA to various substrates. For example, N-acetylation of isoniazid. Genetic polyporphism occurs with N-acetyltransferase. www.indiandentalacademy.com
  118. 118. N-Acetyltransferase www.indiandentalacademy.com
  119. 119. N-Acetyltransferase • The dog cannot acetylate aromatic amino compounds because it lacks the appropriate isoenzyme of NAT www.indiandentalacademy.com
  120. 120. SUGAR CONJUGATION www.indiandentalacademy.com
  121. 121. Conversion of 6-Mercaptopurine to a Nucleotide www.indiandentalacademy.com
  122. 122. METHYLATION www.indiandentalacademy.com
  123. 123. S-Adenosylmethionine Cytosolic enzymes such as catechol-O-methyl transferase (COMT) and phenylethanolamine-N-methyl transferase (PNMT) conducts the donation of the methyl group from the endogenously synthesized SAM to various substrates to form methylated conjugates. Norepinephrine is N-methylated by PNMT to form epinephrine. Norepinephrine, www.indiandentalacademy.com epinephrine, dopamine, and L-DOPA are O-methylated by COMT.
  124. 124. Methyltransferases • A family of soluble enzymes that conducts – – – N-methylation; N-CH3 O-methylation; O-CH3 S-methylation; S-CH3 • S-adenosylmethionine (SAM)is the endogenous donor molecule. It is demethylated to S-adenosylhomocysteine www.indiandentalacademy.com
  125. 125. N-Methyltransferases PNMT- Phenylethanolamine-N-methyltransferase Norepinephrine PNMT SAM Epinephrine www.indiandentalacademy.com
  126. 126. O-Methylation Of Catecholamines COMT- catechol-O-methyltransferase www.indiandentalacademy.com
  127. 127. O-Methylation of Norepinephrine COMT- catechol-O-methyltransferase www.indiandentalacademy.com
  128. 128. S-Methylation of 6-Mercaptopurine TPMT - thiopurinemethyltransferase; some individuals are deficient in this enzyme that is critically important for the metabolism of this agent www.indiandentalacademy.com
  129. 129. METABOLISM OF MERCAPTOPURINE (1) 6-Mercaptopurine TMPT 6-Methylmercaptopurine • TMPT -Thiomethylpurinetransferase – Conducts S-methylation of the substrate – Found in RBC’s – Isoforms exist • active enzyme • inactive enzyme www.indiandentalacademy.com
  130. 130. AMINO ACID CONJUGATION www.indiandentalacademy.com
  131. 131. AMINO ACID CONJUGATION (mitochondria) www.indiandentalacademy.com
  132. 132. Multiple Metabolic Pathways Exist for Aspirin’s Metabolism Hydolysis of aspirin produces salicyclic acid, as seen in the next slide www.indiandentalacademy.com
  133. 133. Salicyluric Acid is the Glycine Conjugate of Aspirin Salicyluric acid, the glycine conjugate of salicyclic acid, is the main metabolite of aspirin. Approximately 76% of aspirin is metabolized through amino acid conjugation. www.indiandentalacademy.com
  134. 134. Acetyl Salicylic Acid (Aspirin) Metabolism • Salicylic acid the hydrolytic product of acetyl salicylic acid. Salicylic acid is further metabolized • Salicyl uric acid is the glycine conjugate and the main metabolite of aspirin. About 75% of aspirin is metabolized by this pathway • Other metabolites of aspirin – the acyl glucuronide conjugate of salicylic acid (salicylic acid glucuronide) – the phenol glucuronide conjugate of salicylic acid (salicyl phenol glucuronide) – the ring hydroxylated product of salicylic acid (gentisic acid) – the ring hydroxylated product of the glycine conjugate (gentisuric acid www.indiandentalacademy.com
  135. 135. TRANSULFURATION www.indiandentalacademy.com
  136. 136. TRANSULFURATION www.indiandentalacademy.com
  137. 137. GLUTATHIONE CONJUGATION www.indiandentalacademy.com
  138. 138. DRUG INTERACTION WITH GLUTATHIONE www.indiandentalacademy.com mercapturate metabolite of drug
  139. 139. MERCAPTURIC ACID FORMATION • Conjugation of substrate to glutathione by the enzyme glutathione transferase • Hydrolytic removal of glutamic acid by glutamyl transpeptidase • Hydrolytic removal of glycine by cysteinyl glycinase • Acetylation of the cysteinyl substrate by N-acetyltransferase to form the N-acetylated cysteinyl conjugate of substrate; substrate referred to as a “mercapturate” www.indiandentalacademy.com
  140. 140. ACETAMINOPHEN METABOLISM www.indiandentalacademy.com
  141. 141. Bioactivation of Acetaminophen www.indiandentalacademy.com
  142. 142. ACETAMINOPHEN AND ITS PHASE II METABOLITES The sulfate and glucuronide conjugates of acetaminophen are the major metabolites. High doses of acetaminophen can exhaust the metabolic pathways that produce these conjugates, allowing more of the parent drug to undergo the phase I metabolic pathway which is involved in bioactivation and toxication. www.indiandentalacademy.com
  143. 143. ACETAMINOPHEN AND ITS PHASE I METABOLITES www.indiandentalacademy.com
  144. 144. ACETAMINOPHEN AND ITS PHASE I METABOLITES- pt2 The minor metabolite (4% of acetaminophen), N-hydroxyacetaminophen, is always produced by microsomal cytochrome P450. It rearranges to the electrophile N-acetylbenzoquinoneimine, which in turn reacts with the sulfhydryl group of glutathione. Acetaminophen mercapturic acid is the final metabolite. If tissue glutathione stores are depleted as a result of fasting, intake of excessive doses of acetaminophen or through induction of CYP2E1 as a result of chronic intake of ethanol, the quinone interacts with nucleophilic sites of cellular macromolecules, such as proteins. Liver necrosis is the result. Regular intake of acetaminophen during fasting or chronic ethanol intake should be avoided. N-acetylcysteine is the antidote for acetaminophen poisoning. It reacts with the electrophile. A small amount of acetaminophen is reported to undergo deacetylation to the phase 1 metabolite paminophenol. www.indiandentalacademy.com
  145. 145. N-ACETYLCYSTEINE FOR ACETAMINOPHEN TOXICITY www.indiandentalacademy.com
  146. 146. CARCENOGENSIS www.indiandentalacademy.com
  147. 147. N-Hydroxylation of AAF N-Hydroxylation of AAF is the first metabolic step towards the development of a carcinogenic agent www.indiandentalacademy.com
  148. 148. Further Metabolism of N-HydroxyAAF Produces Cancer N-HydroxyAAF undergoes phase II metabolism to the ultimate carcingogen. The glucuronide pathway is also involved in carcinogenesis www.indiandentalacademy.com
  149. 149. CYP1A1 Converts Benzopyrene to a Carcinogen www.indiandentalacademy.com
  150. 150. Aflatoxin is Metabolized to a Carcinogenic Agent www.indiandentalacademy.com
  151. 151. FACTORS AFFECTING DRUG METABOLISM www.indiandentalacademy.com
  152. 152. ENZYME INDUCTION www.indiandentalacademy.com
  153. 153. www.indiandentalacademy.com
  154. 154. CORRELATION BETWEEN SLEEPING TIME AND PLASMA T1/2 IN CHRONIC PENTOBARBITAL PRETREATED RABBITS www.indiandentalacademy.com
  155. 155. Factors Affecting Drug Metabolism • 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 www.indiandentalacademy.com
  156. 156. AGE www.indiandentalacademy.com
  157. 157. FACTORS AFFECTING DRUG METABOLISM • Age – Neonates – Children – Elderly www.indiandentalacademy.com
  158. 158. DIET www.indiandentalacademy.com
  159. 159. FACTORS AFFECTING DRUG METABOLISM • 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) www.indiandentalacademy.com
  160. 160. GENETIC VARIATION www.indiandentalacademy.com
  161. 161. Some Enzymes That Exhibit Genetic Variation – Pseudocholinesterase • typical enzyme • atypical enzyme – N-Acetyltransferase (isoniazid is a substrate) • fast acetylation • slow acetylation – Cytochrome P450 2D6 – Cytochrome P450 2C19 – TMPT -Thiomethylpurinetransferase – Dihydropyrimidine Dehydrogenase www.indiandentalacademy.com
  162. 162. STATE OF HEALTH www.indiandentalacademy.com
  163. 163. FACTORS AFFECTING DRUG METABOLISM • State of health – Hepatitis – Liver cancer – Cardiac insufficiency – Uremia • degree of protein binding www.indiandentalacademy.com
  164. 164. Changes In Drug Metabolism As A Consequence Of Hepatic Disease www.indiandentalacademy.com From Principles of Drug Action
  165. 165. GENDER www.indiandentalacademy.com
  166. 166. FACTORS AFFECTING DRUG METABOLISM • Gender – Most studies are performed in the rat. In general, male rats metabolize drugs faster than female rats www.indiandentalacademy.com
  167. 167. DEGREE OF PROTEIN BINDING www.indiandentalacademy.com
  168. 168. FACTORS AFFECTING DRUG METABOLISM • Degree of protein binding – Conditions that displace bound drug from protein allows more of the drug to be accessible to the enzyme for which it serves as a substrate e.g. uremia, low plasma albumin www.indiandentalacademy.com
  169. 169. SPECIES VARIATION www.indiandentalacademy.com
  170. 170. FACTORS AFFECTING DRUG METABOLISM • Species variation – Quantitative – Qualitative www.indiandentalacademy.com
  171. 171. Factors Affecting Drug Metabolism • Species variation – Human beings metabolize amphetamine by deamination; rats and dogs metabolize the drug by aromatic hydroxylation – Guinea pigs have very little sulfotransferase activity, humans have substantial activity – Guinea pigs do not N-hydroxylate substrates; mice, rabbits, dogs do – Hexobarbital is metabolized at different rates by different species www.indiandentalacademy.com
  172. 172. www.indiandentalacademy.com
  173. 173. SUBSTRATE COMPETITION www.indiandentalacademy.com
  174. 174. Factors Affecting Drug Metabolism • Substrate competition – Two or more drugs competing for the same enzyme can affect the metabolism of each other; the substrate for which the enzyme has the greater affinity would be preferentially metabolized www.indiandentalacademy.com
  175. 175. www.indiandentalacademy.com Leader in continuing dental education www.indiandentalacademy.com

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