Introduction

Drug metabolism (biotransformation or detoxication) is the biochemical changes of the drugs and other foreign substances in the body.

This is leading to the formation of different metabolites with different effects.

Some of the compounds are excreted partially unchanged and some are known to be converted to products, which may be more active 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.

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.

Classification of metabolites:

Inactive metabolites Metabolites retain similar activity Metabolites with different activity Bioactivated metabolites (prodrug

technique)

1-Inactive metabolites: Some metabolites are inactive,

i.e. their pharmacological active parent compound become inactive.

Examples:i) Hydrolysis of procaine to p-aminobenzoic acid and

diethylethanolamine results in loss of anesthetic activity of procaine.

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

6-Mercaptopurine 6-Mercapturic acid (inactive)

NH2

O

N

O

NH

N

O

CH3CH3H2N-C6H5-COOH + Et2N-CH2CH2OH

Inactive metabolites

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).

4-Bioactivated metabolites (activation of inactive 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 (active metabolite) 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 antiinflammatory drug (sulfoxide) is reduced to the active sulfide

iii) Benorylate to aspirin and paracetamol

iv) The prodrug enalapril is hydrolysed to enalaprilat (potent antihypertension).

Biotransformation Pathways

Drug metabolism reactions have been divided into two classes:

i) Phase I reaction (functionalization ) and

ii) 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 of ketones and aldehydes to alcohols.

Phase I reactions may increase or decrease or leave unaltered the pharmacological activity of the drugs

1-Oxidation:

Addition of oxygen or removal of hydrogen.

Normally the first and most common step involved in the drug metabolism

Majority of oxidation occurs in the liver and it is possible to occur in intestinal mucosa, lungs and kidney.

Most important enzyme involved in this type of oxidation is cytochrome P450

Increased polarity of the oxidized products (metabolites) increases their water solubility and reduces their tubular reabsorption, leading to their excretion in urine.

These metabolites are more polar than their parent compounds and might undergo further metabolism by phase II pathways

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 to create polar functional groups that can be eliminated in the urine.

Cytochrome P450 system is involved in some reaction. Other reactions are catalyzed by reductases enzymes 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 polar metabolites.

Different enzymes catalyze the hydrolysis of drugs:

Esterase enzymes

Amidase enzymes

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 Alcohol

Esterases are responsible for converting many prodrugs into their active forms.A classical example of ester hydrolysis is the metabolic conversion of aspirin (acetylsalicylic acid) to salicylic acid and acetic acid. COOH

OCOCH3

COOH

OHH2O CH3COOH+

Aspirin Salicylic acid

Acetic acid

2-Amidase enzymes:It is the hydrolysis of amides into amine and acid and

this is called Deamination.Deamination occurs primarily in the liver.

O

C RNH2 H2O

O

C OHR NH3+ +

Amide Water Acid Ammonia

•Amide drugs are more resistant to hydrolysis (or they are not hydrolyzed 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 shorter acting than its amide analogue procainamide administered similarily.

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

Generally phase I reactions provide a functional groups or handle in the molecule that can undergo phase II reactions. Thus, phase II reactions are those in which the functional groups of the original drug (or metabolite formed in a phase I reaction) are masked by a conjugation reaction.

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

Many conjugative enzymes accomplish this objective by attaching small, polar, and ionizable endogenous molecules such as glucuronic acid , sulfate, glycine, glutamine and glutathione to the phase I metabolite or parent drug. The resulting conjugated products are very polar (water soluble), resulting in rapid drug elimination from the body.

Phase II Conjugation Reactions

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

The high-energy molecule consists of a coenzyme which is bound to the endogenous substrate and the parent drug or the drug’s metabolite resulted from phase I reaction.

The enzymes that catalyzed conjugation reactions are called transferases, found mainly in the liver and to a lesser extent in the intestines and other tissues.

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

Exceptions to this are acetylated and methylated conjugates because these phase II reactions (methylation and acetylation) does not generally increase water solubility but serve mainly to terminate or reduce pharmacological activity (they are usually pharmacologically inactive).

Conjugating molecules:o 1- Glucuronic acid conjugation:o It forms O-glucuronides with phenols Ar-OH,

alcohols R-OH, hydroxylamines H2N-OH,and carboxylic acid RCOOH.

o It can form N-glucuronides with sulfonamides, amines, amides, and S-glucuronides with 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 be toxic.

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

mercapturic acid and mostly are excreted in bile. It is important in detoxifying potentially dangerous environmental toxins.

5,6- Methylation and acetylation reactions:

These decrease the polarity of the drugs except tertiary amines which are converted to polar quaternary salts.

The groups susceptible for these reactions are phenols, amines, and thiols.

O-methylation of meta-phenolic OH in catecholamines does not generally increase water solubility but serve

mainly to terminate or reduce pharmacological activity (they are usually pharmacologically inactive).

7- Cholesterol conjugation: For carboxylic acids by ester link formation or for

drug with ester group by trans esterification.

8- Fatty acid conjugation: For drugs with alcohol functional groups by ester

link.

Conjugating molecules:

There are six conjugation pathways:

1)-Glucuronidation: by glucuronyl transferase.O

HOHO

HOOCH

O UDPOH

R X+

O

HOHO

HOOCH

XOH R

X = OH, NR2, CO2H, SH, acidic carbon atomGlucuroinc acid UDP

2)-Sulfate conjugation

OAdenine

P

O

OS

O

HO

O OH

HOH2O3PO

PAPS

+ R X S X

O

HORO

X = OH, arylamine, NHOH

Glucuronyl Transferease catalyses this conjugation reaction

Sulfotransferease catalyses this conjugation reaction

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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

HY = H or CH2CH2CO2H

Acyl coenzyme A

N-acyltransferase catalyses the conjugation reaction

4)-Glutathione conjugation

CS

CoA

O

R+

H2N CO2H

YH

N CO2H

YH

CR

O

HY = H or CH2CH2CO2H

Acyl coenzyme A

Glutathione S-transferase catalyses this conjugation reaction

5)-Methylation

6)-Acetylation

N-acyltransferase catalyses 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 CoA Y =NH2, NHNH2, SO2NH2, CONH2

RX

CR

O

+CS

CoA

O

H3CR X

Extrahepatic metabolism

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

The most common sites include the plasma, GI mucosa, nasal passages, lungs and kidneys. However, metabolism can occur throughout the body.

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Factors influencing Drug Metabolism

Factors influencing Drug Metabolism

1-Chemical Structure : The chemical structure (the absence or presence of certain

functional groups) of the drug determines its metabolic pathways.

2-Species differences (Qualitative & Quantitative): Qualitative differences may result from a genetic deficiency of a

certain enzyme while quantitative difference may result from a difference in the enzyme level.

3-Physiological or disease state: 1-For example, in congestive heart failure, there is decreased

hepatic blood flow due to reduced cardiac output and thus alters the extent of drug metabolism.

2-An alteration in albumin production can alter the fraction of bound to unbound drug, i.e., a decrease in plasma albumin can increase he fraction of unbound free drug and vice versa.

3-pathological factors altering liver function can affect hepatic clearance of the drug.

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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

faster than that in eurpoean or north american people. Fast acetylators are more prone to hepatoxicity than slow acetylator.

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

concentration and may saturate certain metabolic enzymes.

2- when metabolic pathway becomes saturated, an alternative pathway may be pursued.

Factors influencing Drug Metabolism

6-Nutritional status: 1-Low protein diet decreases oxidative reactions or

conjugation reactions due to deficiency of certain amino acids such as glycine.

2-Vitamin deficiency of A,C,E, and B can result in a decrease of oxidative pathway in case of vitamin C deficiency , while vitamin E deficiency decreases dealkylation 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 hexobarbital by decreasing certain drug-metabolizing enzymes.

Factors influencing Drug Metabolism

7-Age:1- Metabolizing enzymes (sp.glucuronide conjugation)are

not fully developed at birth, so infants and young children need to take smaller dosesthan adults to avoid toxic effects.

2-In elderly, metabolizing enzyme systems decline.

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

been observed for certain compounds Metabolism of Diazepam, caffiene, and paracetamol is

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

Factors influencing Drug Metabolism

9-Drug administration route:

1-Orally administered drugs are absorbed from the GIT 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 orally due to hepatic metabolism.

3-IVadministration avoid first pass effect because the drug is delivered directly to the blood stream.

Factors influencing Drug Metabolism

10-Enzyme induction or inhibitionSeveral antibiotics are known to inhibit the

activity of cytochrome P450. Phenobarbitone is known to be cytochrome

P450 enzyme 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 less metabolized and thus serious side effects may appear.

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Strategies to manage drug metabolism

Strategies to manage drug metabolism

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 as nitroglycerine (antiangina drug).

2-Transdermal patches and ointments: provide continuous supply of drug over extended period of time and are useful for rapidly metabolizing drugs suchj as prophylactic nitroglycerine.

3- Intramuscular injections provide a continuous supply of drug over extended period of time such as`lipid soluble esters of estradiol 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

Strategies to manage drug metabolism

2)-Pharmacological strategies

These involve the concurrent use of enzyme inhibitors to decrease

drug metabolism. Sometimes the concurrent use of an additional

agent doesn’t prevent metabolism but prevents the toxicity

caused by metabolites of the therapeutic agent.

1- Levodopa, the aminoacid precursor of dopamine, in the treatment of

Parkinson’s disease. Carbidopa , a dopa decarboxylase inhibitor

2- β-Lactam antibiotics activity is reduced by micoorganisms capable

of secreting β–lactamase enzymes. Clavulanic acid is a β–

lactamase inhibitor used in conjunction with penicillin antibiotics.

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Strategies to manage drug metabolism

3)-Chemical strategiesThese are molecular modifications

involving the addition, deletion or isosteric modification of functional groups.

Examples are: 1-chlorpropamide was designed from

tolbutamide2-Methyl testosterone was designed from

testosterone.

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Prodrugs Prodrugs strategies

Prodrugs are used instead of active form of the

drug to:a) Enhance membrane permeability, b) Reduce drug toxicity c) Overcome /mask bad taste d) Overcome acid sensitivity e) Prolong (short) duration.

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 esters b-Increase oral absorption as by using esters of the highly polar

drugs or N-methylationC-Increase topical absorption of steroids by masking OH group as

esters or acetonides.3-A decrease in water solubility to increase palatability as in

chloramphenicol 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 cefamandole acetate a stable prodrug, while the parent cefamandole is unstable solid dosage form. Hetacillin is another prodrug (for ampicillin ).