Drug Metabolism

By: Dr. Mohsen Bebars

Dr. Mohsen Bebars

Drug Metabolism ( Biotransformation)

➢ It is a process of biochemical changes of drugs or xenobiotics in the body which carried out by specialized metabolizing enzymatic system found in liver and extra hepatic tissues (intestinal mucosa, kidney, skin and lung).

➢ Drugs or xenobiotics metabolism is a set of metabolic pathways that modify their chemical structure to convert them from non-polar, lipid soluble (lipophilic) form to the more polar and water soluble (hydrophilic) metabolites which are easily excreted.

➢ Most of hydrophilic drugs e.g. streptomycin are not bio-transformed and are excreted unchanged (non-enzymatic).

➢Such chemical modifications may decrease or increase the pharmacological activity and half-life of the drug i.e. the resulting modified metabolite may be more active, less active, equally active, inactive or toxic.

➢Drug metabolism is considered as a protective process that eliminate drugs and foreign chemicals outside the body and it may lead to formation of inactive and non-toxic metabolite (detoxification).

➢The rate of drug metabolism determines the duration of drug action, intensity of drug action, elimination and toxicity.

Dr. Mohsen Bebars

Sites of drug metabolism in the human body:

a) Liver: is the main route of Hepatic drug metabolism by metabolizing enzyme

b) Extra hepatic tissues: Intestinal mucosa, Kidney , Lung and skin

sulfate conjugation

Intestine

Reduction of aromatic Azo and Nitro drugs

Sulfation and GlucurondationDr. Mohsen Bebars

Hepatic and extra hepatic microsomal enzymes : ( Oxidation, Conjugation)

Hepatic non microsomal enzymes : ( acetylation, sulfation, GSH, Alcohol / Aldehyde dehydrogenase, hydrolysis, oxidation / reduction )

Dr. Mohsen Bebars

Microsomal enzymes Non-Microsomal enzymes

Located in Smooth Endoplasmic Reticulum: manly in Liver and kidney.

Located in Cytoplasm & Mitochondria of hepatic cells and other tissues.

Non synthetic - phase 1 reaction : Non synthetic - phase 1 reaction :

Most oxidation and reduction Some hydrolysis

Some oxidation and reduction Most hydrolysis

Synthetic - phase II reaction: Synthetic - phase II reaction:

- Only glucuronide conjugation - All except glucuronide conjugation

First Pass Metabolism(First pass effect, Presystemic effect)

➢It is a phenomenon of rapid uptake and metabolism of oral drugs carried out by

liver and gut wall immediately after enteric absorption and before reaching the

systemic circulation resulting a great reduction of drug concentration.

➢First pass metabolism may results a large fraction of drug become as inactive

metabolite and small fraction of bioactive metabolite or drug only reach to the

systemic circulation. This on turn leads to significant decrease of drug

bioavailability and short duration of action.

Dr. Mohsen Bebars

➢Examples of dugs exposed to first pass metabolism when taken by

oral route: Lidocaine, nitroglycerine and propranolol.

➢Some drug like Lidocaine becomes non effective by first pass

metabolism when taken by oral route of administration.

Dr. Mohsen Bebars

Bypassing of First Pass MetabolismA. By Changing the route of drug administration to make it away from

distribution in GIT fluids and first pass effect of liver

I. Giving the drug in sublingual on buccal routes where the drug is absorbed by oral

mucosa in both methods, that’s why nitroglycerine is taken sublingually to bypass

the liver.

II. Giving the drug by injection root like lidocaine .

B. Use of the prodrug i.e. use of propranolol hemi-succinate or acetate as

prodrug to bypass the liver effect.

Dr. Mohsen Bebars

Phases of drug metabolism

• Metabolism of Xenobiotics or drugs is often proceed in two phases ended

by metabolite excretion to detoxify Xenobiotics and remove them from

the cell.

Dr. Mohsen Bebars

Phase I metabolism:Functionalization or modification

• Phase I reactions are carried out by a variety of enzymes to introduce a new or modified polar function group (OH, NH2, COOH and SH) throughoxidative, reductive and hydrolysis reaction.

• Introducing a new polar functional group to drug molecule carried out

either by:

a. Direct introduction of such functional group e.g. aliphatic and aromatic

hydroxylation.

b. Modifying the existing functional group e.g. hydrolysis of ester to yield free

COOH group.

Dr. Mohsen Bebars

• These enzymatic reactions convert the non-polar, Lipophilic drug to

polar, hydrophilic metabolite which is easily excreted.

• However, many of phase I metabolites are not eliminated rapidly and

undergo subsequent reactions (conjugation) to form a highly polar

conjugate.

Dr. Mohsen Bebars

• Involve conjugation of the activated metabolite with endogenous substance such as:

• Such conjugation reactions are carried out by transferases enzymes.

• Conjugation reaction occur on the new polar sites COOH, OH, NH2 and SHof drugs e.g. Glucuronidation.

Dr. Mohsen Bebars

• Glucuronic Acid • Glutathione GSH

• Sulfate • Glycine

• Methylation • Acetylation

Phase II metabolism: Conjugation Reactions.

➢The formed conjugate metabolites are more polar and readily excreted

either by kidney (in urine) or by liver (in bile).

➢Conjugation reaction products (conjugate adduct) are having increased

molecular weight and tend to be less active than their parent substances.

➢Addition of large anionic group such as GSH detoxify the reactive

electrophile and produce more polar and readily excreted metabolite.

Dr. Mohsen Bebars

Dr. Mohsen Bebars

Dr. Mohsen Bebars

Drug metabolism pathways

Dr. Mohsen Bebars

Dr. Mohsen Bebars

Phase I Reactions Oxidative, Reductive and Hydrolysis

Purpose : introducing a polar function group into drug molecule through different reactions

A) Oxidative reactions: ( oxidative biotransformation) • It is the most common type in drug metabolism involved hydroxylation.• Represented by the following equation:

RH+NADPH+O2+H+ ROH+NADP++H2ODrug Metabolite

• The reaction is catalyzed by a set of enzymes complexes called cytochrome P450 monooxygenase enzyme system or mixed function oxidases (MFO) or microsomal hydrolase.

MFO is mixed function oxidases found in liver and extra hepatic tissues

MFOCatalyst

Dr. Mohsen Bebars

Dr. Mohsen Bebars

MFO (multifunctional oxidases) components :

• Cytochrome P-450

➢ Responsible for transferring oxygen atom to the substrate RH

➢ It is highly concentrated in liver and also present in extra hepatic tissues e.g.

kidney, lung and intestine

• Cofactors:

Supplying the electrons needed in the metabolic oxidation

NADPH. Dependent Cytochrome P-450 Reductase

NADH. Limited Cytochrome b5

Dr. Mohsen Bebars

• CYP-450 Enzyme nomenclature:

➢ CYP: Cytochrome P450 Enzymes.

➢ CYP 1: Family.

➢ CYP1A: Subfamily.

➢ CYP 1A2: Individual Enzyme in the subfamily.

Dr. Mohsen Bebars

1- Oxidation of Aromatic Molecules ( Arenes)By Hydroxylation to their phenolic metabolites ( Arenoles)

Dr. Mohsen Bebars

Rules of Aromatic Oxidation:-(Microsomal Aromatic Hydroxylation)

• Occurs at the para-position of the aromatic ring.

• Occurs at Ortho-position when the para one is occupied.

Dr. Mohsen Bebars

The reaction proceeded most rapidly in activated aromatic ring (attached with OH and NH2 group).

• The reaction proceeded slowly with deactivated aromatic ring (attached with CL, COOH and SO2NHR) .

Dr. Mohsen Bebars

The reaction proceeded in the more activated aromatic ring in case of drug having two aromatic moiety.

Dr. Mohsen Bebars

Fate of Arene Oxide:-

Dr. Mohsen Bebars

Dr. Mohsen Bebars

2- Oxidation of Olefins:-• Olefins Unstable epoxide Dihydroxy compound

• Some of epoxide metabolite linked covalently with DNA, RNA and protein resulting Hepatotoxic product eg Aflatoxin B1.

Metabolic Oxd.

EH

Enzymatic Hyrdation

Dr. Mohsen Bebars

Dr. Mohsen Bebars

3- Oxidation of Benzylic Carbon Atom:-• The Benzylic Carbon atom upon metabolic oxidation gives the

corresponding primary alcohol which upon oxidation give Aldehyde and Carboxylic acid while secondary alcohol oxidized to Ketones.

Dr. Mohsen Bebars

4- Oxidation of Allylic Carbon Atom:-• By Allylic hydroxylation at the Allylic carbon center eg Marijuana

which have three allylic carbon centers.

Dr. Mohsen Bebars

5- Oxidation of Carbon Atom Alpha to Carbonyl and Imines:-• By hydroxylation of such alpha carbon atom eg Benzodiazepines.

• Hydroxylation of alpha carbon atom to carbonyl occurs at limited extend egGlutethimide (Hypnotic).

Dr. Mohsen Bebars

6- Oxidation of Aliphatic and Alicyclic Carbon Atoms ( Side Chain Oxidation):-

• Aliphatic side chain Alcohol metabolite

eg Barbiturates and Sulfonyl urea

Aldehyde or carboxylic acid

Oxidation

At terminal methyl group commonly at ω-1 carbon atom

Further oxidation

Dr. Mohsen Bebars

• Cyclohexyl group hydroxycyclohexyl metaboliteMFO alicyclic

ozidation

Dr. Mohsen Bebars

7- Oxidation involving Carbon- Heteroatom system: C-N , C-O, C-S• This type of oxidation is carried out in two steps:

A- hydroxylation of alpha carbon atom attached to hetero atom resulting unstable hydroxy intermediate

B- decomposition of such intermediate with cleavage of C-heteroatom bond

Dr. Mohsen Bebars

• According to the nature of hetero atom this type of oxidation is classified into :

A- oxidative N-dealkylation

✓Involves oxidation of sec. and ter. Amine

✓Gradual removal of alkyl group

✓Bisdealkylation my occur but very slowly

Dr. Mohsen Bebars

B- Oxidation involving C-O system

proceeded by C-O cleavage to hydroxy metabolites ( O-demethylation)

Dr. Mohsen Bebars

C- Oxidative S-dealkylation

• Such oxidation occurs in 2 steps:

A- hydroxylation of Alfa Carbon resulting unstable carbinolintermediate

B- cleavage of C- S to the meracapto metabolite

Dr. Mohsen Bebars

8- Oxidative dehalogenation

Such reaction is carried out in the presence of:

NADPH , O2-dependant and cytochrome P-450

The carbon to be oxidized must carry hydrogen atom which converted to: unstable carbinol

Removal of halogen and hydrogen atoms leads to formation of ketone

Eg chloroform

Dr. Mohsen Bebars

9- oxidative deamination

Occurs in 2 steps :

A- hydroxylation of Alpha Carbon resulting carbinol amine intermediate

B-cleavage of C-N to carbonyl metabolite and ammonia

Dr. Mohsen Bebars

10- Oxidation of hetero atoms ( N,S)• This microsomal oxidation increasing the polarity of the metabolite

• N oxidation of primary amine give the corresponding nitro metabolite

Also drugs as pheneramine and amantadine are metabolized by N-oxidation

Dr. Mohsen Bebars

• Secondary amines are metabolized by N-hydroxylation eg Paracetamol

• Continuous misuse or over dose of paracetamol in addition to Glutathione ( GSH) depletion leads to liver necrosis

Dr. Mohsen Bebars

N-acetyl benzoquinone imine(NABQI)

S-Oxidation

• Sulfur atom in aliphatic and cyclic system is oxidized to sulfoxide and sulfone

Dr. Mohsen Bebars

Oxidative desulfurization

• Conversion of C=S to C=O ( replacement of sulfur to oxygen)

Dr. Mohsen Bebars

Dr. Mohsen Bebars

Non Microsomal Enzymes

• Hepatic non microsomal enzymes include :

( Acetylation, sulfation, GSH, alc. / ald. Dehydrogenase , hydrolysis , oxd/red.)

• Oxidation of alcohols and aldehydes by alcohol dehydrogenase and aldehyde dehydrogenase in the presence of NAD+ and NADP+ as co enzymes

Dr. Mohsen Bebars

Dr. Mohsen Bebars