1. Metabolic Changes of Drugs
Books: 1. Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry 11th ed. Lippincott, Williams & Wilkins ed.
2. Foye’s Principles of Medicinal Chemistry
3- Burger's Medicinal Chemistry &Drug Discovery.
Prof. Faris T. Abachi ( PHD Pharmacy)
3rd Year Pharmacy
2017

2. outlines Introduction Definitions. General pathways of drug metabolism
Sites of drug biotransformation
Role of Cytochrome P-450 Enzymes
Classification.

3. Introduction
Metabolism play a central role in the elimination of drugs and other foreign compounds ( Xenobiotics) from the body.
A solid understanding of drug metabolism pathways is an essential tool for pharmacists in their role of selecting and monitoring appropriate drug therapy for their patients.

4. Definitions
Biochemically speaking: Metabolism means Catabolism (breaking down of substances) + Anabolism (building up or synthesis of substances)
But when we speak about drug metabolism, it is only catabolism
That is drug metabolism is the break down of drug molecules
So what is building the drug molecules? We use the word “synthesis”, then
 Biotransformation: It is a specific term used for chemical transformation of xenobiotics in the body/living organism.• a series of enzyme-catalyzed processes—that alters the physiochemical properties offoreign chemicals (drug/xenobiotics) from those that favor absorption across biologicalmembranes (lipophilicity) to those favoring elimination in urine or bile (hydrophilicity )

5. What Roles are Played by Drug Metabolism?
Xenobiotics : These are all chemical substances that are not nutrient for body (foreign to body) and which enter the body through ingestion, inhalation or dermal exposure.They include : drugs, industrial chemicals, pesticides, pollutants, plant and animal toxins, etc.animal toxins,
One of four pharmacokinetic parameters, i.e., absorption, distribution, metabolism and excretion (ADME)
Elimination of Drugs: Metabolism and excretion together are elimination
Xenobiotics : These are all chemical substances that are not nutrient for body (foreign to body) and which enter the body through ingestion, inhalation or dermal exposure.They include : drugs, industrial chemicals, pesticides, pollutants, plant and animal toxins, etc
Many drugs are metabolically activated (Prodrugs)
Sometimes drugs become more toxic and carcinogenic

6. Sites/Organs of drug metabolism
 The major site of drug metabolism is the liver (microsomal enzyme systems of hepatocytes)Secondary organs of biotransformation• kidney (proximal tubule)• lungs (type II cells)• testes (Sertoli cells)• skin (epithelial cells); plasma. nervous tissue (brain); intestines
Enzymes are divided into TWO types:

7. 1-Microsomal enzymes:
The endoplasmic reticulum (especially smooth endoplasmic reticulum) of liver and other tissues contain a large variety of enzymes, together called microsomal enzymes(microsomes are minute spherical vesicles derived from endoplasmic reticulum after disruption of cells by centrifugation, enzymes present in microsomes are called microsomal enzymes).

8. 2- Non-microsomal enzymes:
Enzymes occurring in organelles/sites other than endoplasmic reticulum (microsomes) are called non-microsomal enzymes.These are usually present in the cytoplasm, mitochondria, etc. and occur mainly in the liver, Gl tract, plasma and other tissues.They are usually non-specific enzymes that catalyse few oxidative reactions, a number of reductive and hydrolytic reactions, and all conjugative reactions other than glucuronidation

9. General pathways of drug metabolism
Drug metabolism reactions have been divided into TWO categories
PHASE I ; Functionalization
PHASE II ; Conjugation

10. Phase l Oxidation reactions
Aromatic, olefins, benzylic, alicyclic, c-c hetero atoms , N – oxidation, S oxidation, ..
Reduction reactions
Aldehydes, ketones, nitro, azo ,..
Hydrolytic reactions
Hydrloysis of esters & amides

11. Phase II Glucuronic acid conjugation Sulfate conjugation
Glycine, glutamine A.A conjugation
Glutathione or mercapturic acid conjugation
Acetylation
Methylation

12. Compare between phase I &ll
Phase ll
Phase l
Small
large
Polar
Non-polar ( lipophilic )
Excretion to the urine
Not active
Metabolite to another product
active

13. Metabolite activity Examples and notes Inactive (detoxification)
Similar activity to the drug
Different activity
Toxic metabolites
Routes that result in the formation of inactive metabolites are often referred to as detoxification.
The metabolite may exhibit either a different potency or duration of action or both to the original drug.

14. Sites of Drug Metabolism
Liver: Major site, well organized with all enzyme systems
The first-pass effect
Following drugs are metabolized extensively by first-pass effect: Isoproterenol, Lidocaine Meperidine, Morphine, Pentazocine, Propoxyphene, Propranolol, Nitroglycerin, Salicylamide
Intestinal Mucosa: The extra-hepatic metabolism, contains CYP3A4 isozyme
Isoproterenol exhibit considerable sulphate conjugation in GI tract
Levodopa, chlorpromazine and diethylstilbestrol are also reportedly metabolized in GI tract
Esterases and lipases present in the intestine may be particularly important carrying out hydrolysis of many ester prodrugs
Bacterial flora present in the intestine and colon reduce many azo and nitro drugs (e.g., sulfasalazine)
Intestinal b-glucuronidase can hydrolyze glucuronide conjugates excreted in the bile, thereby liberating the free drug or its metabolite for possible reabsorption (enterohepatic circulation or recycling)

15. Enzymes Involved in Drug Metabolism
CYP450, Hepatic microsomal flavin containing monooxygenases (MFMO or FMO) Monoamine Oxidase (MAO) and Hydrolases
Cytochrome P450 system: localized in the smooth endoplasmic reticulum.
Cytochrome P450 is a Pigment that, with CO bound to the reduced form, absorbs maximally at 450nm
Cytochromes are hemoproteins (heme-thiolate) that function to pass electrons by reversibly changing the oxidation state of the Fe in heme between the 2+ and 3+ state and serves as an electron acceptor–donor
P450 is not a singular hemoprotein but rather a family of related hemoproteins. Over 1000 have been identified in nature with ~50 functionally active in humans with broad substrate specificity
Simplified apoprotein portion
Heme portion with activated Oxygen

16. Cytochrome P450: Naming
Before we had a thorough understanding of this enzyme system, the CYP450 enzymes were named based on their catalytic activity toward a specific substrate, e.g., aminopyrine N-demethylase now known as CYP2E1
Currently, all P450’s are named by starting with “CYP” (CYtochrome P450, N1, L, N2 - the first number( Arabic number ) is the family (>40% homology), the letter is the subfamily (> 55% homology), and the second number is the isoform. The majority of drug metabolism is by ~10 isoforms of the CYP1, CYP2 and CYP3 families in humans
Major human forms of P450: Quantitatively, in the liver the percentages of total P450 protein are: CYP3A4 – 28%, CYP2Cx – 20%, CYP1A2 – 12%, CYP2E1 – 6%, CYP2A6 – 4%, CYP2D6 – 4%
By number of drugs metabolized the percentages are: CYP3A4 – 35%, CYP2D6 – 20%, CYP2C8 and CYP2C9 – 17%, CYP2C18 and CYP2C % CYP 1A1 and CYP1A2 -10%, CYP2E1 – 4%, CYP2B6 – 3%
How do you determine the styre

17. Drug Interactions & Metabolism
The drug interactions depend upon:
the isoform(s) required by the drug in question,
the isoforms altered by concomitant therapy,
the type of enzyme alteration (induction or inhibition).

18. General Metabolic Pathways
Oxidation
Aromatic moieties
Olefins
Benzylic & allylic C atoms and a-C of C=O and C=N
At aliphatic and alicyclic C
C-Heteroatom system
C-N (N-dealkylation, N-oxide formation, N-hydroxylation)
C-O (O-dealkylation)
C-S (S-dealkylation, S-oxidation, desulfuration)
Oxidation of alcohols and aldehydes
Miscellaneous
Hydrolytic Reactions
Esters and amides
Epoxides and arene oxides by epoxide hydrase
Phase II - Conjugation
Phase I - Functionalization
Drug Metabolism
Reduction
Aldehydes and ketones
Nitro and azo
Miscellaneous
Glucuronic acid conjugation
Sulfate Conjugation
Glycine and other AA
Glutathion or mercapturic acid
Acetylation
Methylation

19. Tetrahydrocannabinol (D1-THC) Metabolism
The metabolite is polar, ionisable and hydrophilic

20. Oxidative Reactions

21. Hydroxylation is the primary reaction mediated by CYP450
Hydroxylation can be followed by non-CYP450 reactions including conjugation or oxidation to ketones or aldehydes, with aldehydes getting further oxidized to acids
Hydroxylation of the carbon α to heteroatoms often lead to cleavage of the carbon – heteroatom bond; seen especially with N, O and S, results in N–, S– or O–dealkylation.
Must have an available hydrogen on atom that gets hydroxylated, this is important!!!

22. Aromatic HydroxylationOH
Epoxide Hydrase OH
Epoxide Hydrase
Mixed function oxidation of arenes to arenols via an epoxide intermediate arene oxide
Major route of metabolism for drugs with phenyl ring
Occurs primarily at para position
Substituents attached to aromatic ring influence the hydroxylation
Activated rings (with electron-rich substituents) are more susceptible while deactivated (with electron withdrawing groups, e.g., Cl, N+R3, COOH, SO2NHR) are generally slow or resistant to hydroxylation

23. HOME WORK Oxidation of Benzene Ring.
1- Phenytoin
2-Warfarin
3-Propanolol
4-phenybutazone
5- Steroid ( 17-α- Ethyinyestradiol)
6- Atrovastain

24. Amphetamine
Phenytoin
p-hydroxyphenytoin
Warfarin sodium
17-a-Ethinylestradiol
Propranolol
Phenylbutazone
Atorvastatin