[3]-drug metabolism-lect.ppt

8/10/2019 [3]-Drug Metabolism-Lect.ppt

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Introduction

Drug metabolism (biotransformation or detoxication)isthe biochemical changes of the drugs and other foreignsubstances in the body.

This is leading to the formation of different metabolites with

different effects.

Some of the compounds are excreted partially unchanged andsome are known to be converted to products, which may be moreactive or more toxic than the parent compounds.

The liver is the major site of drug metabolism, but specific

drugs may undergo biotransformation in other tissues.


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Importance

Drug metabolism is needed to convert non-polar

lipophilic compounds (lipid soluble) which the body

cannot excrete into more polar hydrophilic compounds

(water soluble) which the body can excrete them in

short period of time.

Because if the lipid soluble non-polar compounds are

not metabolized to the polar water soluble compounds,

they will remain in the blood and tissues and maintain

their pharmacological effects for an indefinite time.


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1-Inactive metabolites: Some metabolites are inactive,i.e. their pharmacological active parent compound become

inactive.

Examples:

i) Hydrolysis of procaine top-aminobenzoic acid anddiethylethanolamine results in loss of anesthetic activity ofprocaine.

ii) Oxidation of 6-mercaptopurine to 6-mercapturic acid resultsin loss of anticancer activity of this compound.

6-Mercaptopurine 6-Mercapturic acid (inactive)

NH2

O

N

O

NH

N

O

CH3CH3

H2N-C6H5-COOH + Et2N-CH2CH2OHInactive metabolites


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2-Metabolites retain similar activity:Some metabolite retain the pharmacological activity of their parent

compounds to a greater or lesser degree.

Examples:i) Codeine is demethylated to the more active analgesic morphine

ii) Phenacetin is metabolized to more active paracetamol

iii) Imipramine is demethylated to the equiactive antidepressant

desipramine.

3-Metabolites with different activity:Some metabolites develop activity different from that of their

parent drugs.

Examples:i) Iproniazid (antidepressant) is dealkylated to isoniazid

(antitubercular)

ii) Retinoic acid (vitamin A) is isomerized to isoretinoic acid (anti-acne agent).


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4-Bioactivated metabolites (activation ofinactive drugs):

Some inactive compounds are converted to active drugs within

the body.These compounds are called prodrugs.

Prodrugs may have advantages over the active form (activemetabolite) as more stable, having better bioavailability or

less side effects and toxicity.Examples:i) Levodopa (antiparkinson disease) is decarboxylated in the

neuron to active dopamine

ii) The prodrug sulindac a new non steroidal antiinflammatorydrug (sulfoxide) is reduced to the active sulfide

iii) Benorylate to aspirin and paracetamol

iv) The prodrug enalapril is hydrolysed to enalaprilat (potent

antihypertension).


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Biotransformation Pathways

Drug metabolism reactions have been divided into two classes:

i)

Phase I reaction (functionalization ) andii) Phase II reaction (conjugation)

Phase I reaction: Polar functional groups are either

introduced into the molecule or modified by oxidation,

reduction or hydrolysis.

Or convert lipophilic molecules into more polar molecules by

introducing or exposing polar functional groups.

E.g. aromatic and aliphatic hydroxylation or reduction ofketones and aldehydes to alcohols.

Phase I reactions may increase or decrease or leave

unaltered the pharmacological activity of the drugs


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1-Oxidation:

Addition of oxygen or removal of hydrogen.

Normally the first and most common step involved in the drugmetabolism

Majority of oxidation occurs in the liver and it is possible to occur in

intestinal mucosa, lungsand kidney.

Most important enzyme involved in this type of oxidation iscytochrome P450

Increased polarityof the oxidized products (metabolites) increases

their water solubility and reduces their tubular reabsorption,

leading to their excretion in urine.These metabolites are more polarthan their parent compounds and

might undergo further metabolism by phase II pathways


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2- Reduction:

is the converse of oxidation (i.e. removal of oxygen or

addition of hydrogen).

E.g. reduction of aldehydes and ketones, reduction of nitro

and azo compounds.

It is less common than oxidation, but the aim is same tocreate polar functional groups that can be eliminated in

the urine.

Cytochrome P450 system is involved in some reaction.

Other reactions are catalyzed by reductasesenzymes

present in different sites within the body.


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3-Hydrolysis:

It is the reaction between a compound and water.

The addition of water across a bond also gives more polarmetabolites.

Different enzymes catalyze the hydrolysis of drugs:

Esterase enzymesAmidase enzymes


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1- Esterase enzymes:

Usually present in plasma and various tissues, are nonspecific and

catalyze de-esterification. Hydrolysis of nonpolar esters into two

polar and more water soluble compounds (i.e. acid and alcohol).

O

C ORCH3 H2O

O

C OHCH3 ROH+ +

Ester of acetic acid Acetic acid Alcoh

Esterases are responsible for converting many prodrugs intotheir active forms.A classical example of ester hydrolysis is the metabolic

conversion of aspirin (acetylsalicylic acid) to salicylic acid andacetic acid. COOH

OCOCH3

COOH

OH

H2O CH3COOH+

Aspirin Salicylic acidAcetic acid


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2-Amidase enzymes:

It is the hydrolysis of amides into amine and acid and this iscalled Deamination.Deamination occurs primarily in the liver.

O

C RNH2 H2O

O

C OHR NH3+ +

Amide Water Acid Ammo

Amide drugs are more resistant to hydrolysis (or they are nothydrolyzed until they reach the liver) than ester drugs which

they are susceptible to plasma esterase.

The duration of actions of ester drugs are less than the

amide analogues.Example:Procaine (ester type) injection or topical is usually shorteracting than its amide analogue procainamide administeredsimilarily.


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Phase II conjugation ReactionsWhen phase I reactions are not producing sufficiently hydrophilic(water soluble) or inactive metabolites to be eliminated from thebody, the drugs or metabolites formed from phase I reactionundergoes phas II reactions.

Generally phase I reactions provide a functional groups or handle inthe molecule that can undergo phase II reactions. Thus, phase IIreactions are those in which the functional groups of the original

drug (or metabolite formed in a phase I reaction) are masked by aconjugation reaction.

Phase II conjugation reactions are capable of converting thesemetabolites to more polar and water soluble products.

Many conjugative enzymes accomplish this objective by attaching small,polar, and ionizable endogenous moleculessuch as glucuronic acid ,sulfate, glycine, glutamine and glutathioneto the phase I metaboliteor parent drug. The resulting conjugated products are very polar (watersoluble), resulting in rapid drug elimination from the body.

Ph II C j ti R ti


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Phase II Conjugation Reactions

These reactions require both a high-energy molecule and an enzyme.

The high-energy moleculeconsists of a coenzyme which is bound to theendogenous substrate and the parent drug or the drugs metaboliteresulted from phase I reaction.

The enzymes that catalyzed conjugation reactions are called

transferases, found mainly in the liver and to a lesser extent in theintestines and other tissues.

Most conjugates are biologically inactive and nontoxic because they arehighly polar and unable to cross cell membrane.

Exceptions to this are acetylated and methylatedconjugatesbecause these phase II reactions(methylation and acetylation) doesnot generally increase water solubility but serve mainly to terminate orreduce pharmacological activity (they are usually pharmacologicallyinactive).


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Conjugating molecules:

o 1- Glucuronic acid conjugation:

o It forms O-glucuronideswith phenols Ar-OH,alcohols R-OH, hydroxylamines H2N-OH,andcarboxylic acid RCOOH.

o It can form N-glucuronideswith sulfonamides,

amines, amides, and S-glucuronideswith thiols.o 2-Sulfate conjugation:o It is less common.o It is restricted to phenols, alcohols, arylamines, and

N-hydroxyl compounds.o But primary alcohols and aromatic hydroxylamines

can form unstable sulfate conjugates which can betoxic.


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Conjugating molecules:

3-Amino acid conjugation: By the formation of peptide link. With glycine or

glutamine.

4- Glutathione conjugation:

It reacts with epoxides, alkylhalides, sulfonates,disulfides, radical species.

These conjugates are converted to mercapturicacid and mostly are excreted in bile. It isimportant in detoxifying potentially dangerousenvironmental toxins.


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Th i j ti th


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There are six conjugation pathways:

3)-Amino acid conjugation:

CS

CoA

O

R+

H2N CO2H

YH

N CO2H

YH

CR

O

H

Y = H or CH2CH2CO2HAcyl coenzyme A

N-acyltransferasecatalyses the conjugation reaction

4)-Glutathione conjugation

C

S

CoA

O

R

+

H2N CO2H

YH

N CO2H

YH

C

R

O

H

Y = H or CH2CH2CO2HAcyl coenzyme A

Glutathione S-transferase catalyses this conjugation

reaction


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5)-Methylation

6)-Acetylation

N-acyltransferasecatalyses the conjugation reaction

Methyltransferase catalyses this conjugation reaction

OAdenine

S+

NH2

HO2C

CH3

HOH2O3PO

R X+ R X CH3

SAM

X = OH, NH2, SH

Aceyl CoAY =NH2, NHNH2, SO2NH2, CONH2

RXCR

O

+CS

CoA

O

H3CR X


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Extrahepatic metabolism

Refers to drug biotransformation that takesplace in tissues other than the liver.

The most common sites include the plasma, GImucosa, nasal passages, lungs and kidneys.However, metabolism can occur throughoutthe body.


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Factors influencing Drug

Metabolism


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F t i fl i D M t b li


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Factors influencing Drug Metabolism 4-Genetic variations:

Isoniazid is known to be acetylated by N-acetyltransferase into inactive metabolite.

The rate of acetylation in asian people is higher or fasterthan that in eurpoean or north american people. Fast

acetylators are more prone to hepatoxicity than slowacetylator.

5-Drug dosing: 1- An increase in drug dosage would increase drug

concentration and may saturate certain metabolicenzymes.

2- when metabolic pathway becomes saturated, an

alternative pathway may be pursued.

F t i fl i D M t b li


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Factors influencing Drug Metabolism

6-Nutritional status:

1-Low protein diet decreases oxidative reactions orconjugation reactions due to deficiency of certain aminoacids such as glycine.

2-Vitamin deficiency of A,C,E, and B can result in a

decrease of oxidative pathway in case of vitamin Cdeficiency , while vitamin E deficiency decreasesdealkylation and hydroxylation.

3-Ca, Mg, Zn deficiencies decreases drug metabolism

capacity whereas Fe deficiency increases it. 4-Essential fatty acid (esp. Linoleic acid) deficiency

reduce the metabolism of ethyl morphine and hexobarbitalby decreasing certain drug-metabolizing enzymes.



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7-Age:1- Metabolizing enzymes (sp.glucuronide conjugation)are not

fully developed at birth, so infants and young childrenneed to take smaller dosesthan adults to avoid toxiceffects.

2-In elderly, metabolizing enzyme systems decline.

8-Gender (sex):Metabolic differences between females and males have been

observed for certain compoundsMetabolism of Diazepam, caffiene, and paracetamol is faster

in females than in males while oxidative metabolism oflidocaine, chordiazepoxide are faster in men than in

females



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9-Drug administration route:

1-Orally administered drugs are absorbed from theGIT and transported to the liver before entering the

systemic circulation. Thus the drug is subjected to

hepatic metabolism (first pass effect) before reaching

the site of action.

2-Sublingually and rectally administered drugs take

longer time to be metabolized than orally taken

drugs.Nitroglycerine is ineffective when taken orallydue to hepatic metabolism.

3-IVadministration avoid first pass effect because the

drug is delivered directly to the blood stream.



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10-Enzyme induction or inhibition

Several antibiotics are known to inhibit the activity ofcytochrome P450.

Phenobarbitone is known to be cytochrome P450enzyme inducer while cimetidine is cyt. P450

inhibitor.If warfarin is taken with phenobarbitone, it will be

less effective.

While if it is taken with cimetidine, it will be lessmetabolized and thus serious side effects mayappear.


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Strategies to manage drugmetabolism

Strategies to manage drug metabolism


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1)-Pharmaceutical strategies:by using different dosage forms to either avoid or compensate for

rapid metabolism.1-Sublingual tablets (through mucous mermbrane) by delivering

drugs directly to blood and bypassing first-pass effect asnitroglycerine (antiangina drug).

2-Transdermal patches and ointments: provide continuous supply of

drug over extended period of time and are useful for rapidlymetabolizing drugs suchj as prophylactic nitroglycerine.

3- Intramuscular injections provide a continuous supply of drug overextended period of time such as`lipid soluble esters ofestradiol and testosterone. Hydrolysis of these prodrugs

produce a steady supply of rapidly metabolized hormones.4-Enteric coated formulation can protect acid-sensitive drugs as

erythromycin.5-Nasal administration allows for the delivery of peptides such as

aerosols since they need only to penetrate the thin epithelial

layer to reach the abundant capillary beds


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3)-Chemical strategies

These are molecular modifications involvingthe addition, deletion or isostericmodification of functional groups.

Examples are:1-chlorpropamide was designed from

tolbutamide

2-Methyl testosterone was designed fromtestosterone.

P d t t i


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Prodrugs strategies

Prodrugs are used instead of active form ofthe

drug to:

a) Enhance membrane permeability,

b) Reduce drug toxicity

c) Overcome /mask bad taste

d) Overcome acid sensitivity

e) Prolong (short) duration.


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Advantages of Prodrugs

1-An increase in water solubility by using sodium succinate esters as

chloramphenicol succinate IV injection.2- An increase in lipid solubilitya-Increase duration of action by using lipid soluble estersb-Increase oral absorption as by using esters of the highly polar drugs

or N-methylationC-Increase topical absorption of steroids by masking OH group asesters or acetonides.

3-A decrease in water solubilityto increase palatability as inchloramphenicol palmitate

4-Decrease GI irritation (side effect) as in aspirin

5-Site specificity as in methyl dopa

6- Increased half-life and chemical stability as in cefamandoleacetate a stable prodrug, while the parent cefamandole is unstables lid d s f H t illi is th d (f i illi )

[3]-drug metabolism-lect.ppt

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