Drug Metabolism (...

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  • 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


    Reduction of aromatic Azo and Nitro drugs

    Sulfation and Glucurondation Dr. 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 Metabolism A. 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) through oxidative, 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


    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


    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 SH of 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++H2O Drug 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

    MFO Catalyst

    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.


    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 hydrox