Biotransformation of Medicinal Products
Session 32: Biotransformation of Medicinal Products.
Total Session Time: 120 minutes
Prerequisites
None
Learning Tasks
By the end of this session students are expected to be able to:
Resources Needed:
SESSION OVERVIEW
|Step |Time |Activity/ |Content |
| | |Method | |
|1 |05 minutes |Presentation |Introduction, Learning Tasks |
|2 |10 minutes |Brainstorming |Definition of Biotransformation |
| | |Presentation | |
|3 |60 minutes |Presentation |Metabolism of Organic Compounds |
|4 |25 minutes |Group |Importance of Biotransformation |
| | |discussion | |
| | |Presentation | |
|5 |10 minutes |Presentation |Key Points |
| 6 |10 minutes |Presentation |Evaluation |
SESSION CONTENTS
STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)
READ or ASK students to read the learning tasks and clarify
ASK students if they have any questions before continuing.
STEP 2: Definition of Biotransformation (10 minutes).
|Activity: Brainstorming (5 minutes) |
| |
|Ask students to brainstorm on the following question: |
| |
|What is Biotransformation? |
| |
|ALLOW few students to respond. |
| |
|WRITE their responses on the flip chart/ board. |
| |
|CLARIFY and SUMMARISE by using the table below |
converts non-polar or lipid soluble compounds to polar or lipid
insoluble compounds.
OR
nutrients, amino acids, toxins, and drugs in the body.
not reabsorbed in renal tubules and are excreted.
more water-soluble, to increase the rate of its excretion through the
urine.
STEP 3: Metabolism of Organic Compounds (60 minutes).
involves mainly 2 processes: one of them is drug metabolism.
enzymes
o Microsomal mixed function oxidases (MFOs) system involved.
o Cytochrome P450 enzymes play important role.
o Lungs
o Kidney
o Intestine
o Placenta
o Skin
o Brain
o Testes
o Muscle
o Spleen
o More polar
o Ionizable
o Water soluble to enhance renal excretion
o More active (for pro drugs)
Drug Metabolism in the Liver
PHASE I REACTIONS
water-soluble & less active to be excreted.
enzyme system known as Cytochrome P450.
o Oxidation
o Reduction
o Hydrolytic cleavage
o Dealkylation
o Ring cyclization
o N-carboxylation
o Dimerization
o Transamidation
o Isomerization
o Decarboxylation
[pic]
hydroxylation. i.e. it proceeds via formation of epoxides to yield 1,2-
dihydrodiols
[pic]
o Carbon atoms attached directly to the aromatic ring are hydroxylated.
[pic]
o Carbon atoms adjacent to Olefinic double bonds (are allylic carbon
atoms) also undergo hydroxylation in a manner similar to Benzylic
Carbons.
[pic]
o Several Benzodiazepines contain a carbon atom (C-3) alpha to both
Hydroxylation.
[pic]
o Terminal hydroxylation of methyl group yields primary alcohols which
undergoes further oxidation to aldehydes and then to carboxylic acid.
[pic]
o Cyclohexane (alicyclic) and piperidine (non-aromatic heterocyclic)
rings are commonly found in a number of molecules.
o Such rings are generally hydroxylated at C-3 or C-4 positions.
[pic]
o Biotransformation of C-N, C-0 & C-S system proceed in one of the two
ways:
dealkylation, oxidative deamination & desulfuration.
o N-DEALKYLATION:
generate an intermediate carbinolamine which rearranges by cleavage of
C-N bond to yield the N dealkylated product and the corresponding
carbonyl of the alkyl group.
[pic]
undergoes dealkylation by removal of smaller alkyl group first.
Example:
o Amides e.g. Diazepam
o N-HYDROXYLATION:
is usually displayed by non-basic nitrogen atoms such as amide
Nitrogen.
[pic]
o S-DEALKYLATION:
dealkylation .IT proceed via α-carbon hydroxylation.
product.
[pic]
o Such a desulfuration reaction is commonly observed in thioamides such
as thiopental
[pic]
o Apart from S-dealkylation, thioethers can also undergo S-oxidation
reaction to yield sulfoxides which may be further oxidized to sulfones
several phenothiazines.
o O-Dealkylation:
carbon hydroxylation to form an unstable hemiacetal or hemiketal
intermediate.
a carbonyl moiety.
[pic]
o In case of ethanol, Oxidation to acetaldehyde is reversible and
further oxidation of the latter to acetic acid is very rapid since
Acetaldehyde is highly toxic and should not accumulate in body.
[pic]
o Oxidative Aromatization /Dehydrogenation
o E.g. Metabolic aromatization of drugs is
[pic]
o This reaction is common with halogen containing drugs such as
chloroform.
o Dehalogenation of this drug yields phosgene which may results in
electrophiles capable of covalent binding to tissue.
[pic]
o Bioreductions are also capable of generating polar functional group
such as hydroxy and amino which can undergo further biotransformation
or conjugation.
o Reduction of carbonyls:
[pic]
[pic]
[pic]
o These two reductions are considered together because the groups are
interconvertible by simple addition or loss of a water molecule.
[pic]
o Reduction of nitro groups proceeds via formation of nitro so and
hydroxyl amine intermediates to yield amines.
[pic]
o Reduction of azo compounds yield primary amines via formation of
hydrazo intermediate which undergo cleavage at N-N bond.
[pic]
o It is reduced to active Sulfanilamide.
o REDUCTIVE DEHALOGENATION:
carbon with the H-atom
[pic]
o REDUCTION OF SULFUR CONTAINING FUNCTIONAL GROUPS:
[pic]
o The reaction doesn’t involve change in the state of oxidation of
substrate.
o The reaction results in a large chemical chain in the substrate
brought about by loss of relatively large fragments of the molecule.
o HYDROLYSIS OF ESTERS AND ETHERS:
o Esters on hydrolyisis yield alcohol & carboxylic acid. The reaction is
catalyzed by esterases.
[pic]
o The reactions catalyzed by amides, involves C-N cleavage to yield
carboxylic acid and amine.
[pic]
PHASE II REACTIONS
glucuronic acid, sulfate, or glycine to form water-soluble compounds
They involve the following metabolic processes;
o Glucuronidation by UDP-Glucuronosyltransferase:
(on -OH, -COOH, -NH2, -SH groups)
o Sulfation by Sulfotransferase:
(on -NH2, -SO2NH2, -OH groups)
o Acetylation by acetyltransferase:
(on -NH2, -SO2NH2, -OH groups)
o Methylation
o Amino acid conjugation (on -COOH groups)
o Glutathione conjugation by Glutathione-S-transferase:
(to epoxides or organic halides)
o Fatty acid conjugation (on -OH groups)
o Glycine Conjugation
o Cyanide Conjugation
o Condensation reactions
o Very important Synthetic reactions carried out by Uridine Di Phosphate
Glucuronosyl Transferase.
o Hydroxyl & Carboxylic acid groups are easily combined with Glucuronic
acid
Glucuronide formation occurs in 2 steps: –
1. Synthesis of an activated coenzyme uridine-5’- diphospho – ( – D-
Glucuronic acid (UDPGA) from UDP- glucose (UDPG).
[pic]
2. Transfer of the glucuronyl moiety from UDPGA to the substrate RXH in
presence of enzyme UDP- glucuronyl transferase to form the conjugate.
[pic]
FACTORS AFFECTING OF BIOTRANSFORMATION OF DRUGS:
o Induction of drug metabolizing enzyme.
o Inhibition of drug metabolizing enzyme
o Environmental chemicals.
o Species differences.
o Strain differences.
o Sex differences.
o Pharmacogenetics – genetic differences in metabolic pathways
affecting individual responses to drugs effects.
o Pregnancy.
o Hormonal imbalance.
o Disease state.
STEP 4: Importance of Biotransformation (25 minutes).
|Activity: Small Group Discussion (10 minutes). |
| |
|DIVIDE students into small manageable groups. |
| |
|ASK students to discuss on the following question. |
| |
|What is the importance of biotransformation? |
| |
|ALLOW students to discuss for 8 minutes. |
| |
|ALLOW few groups to present and the rest to add points not mentioned. |
| |
|CLARIFY and SUMMARIZE by using the contents below |
nutrients (food, oxygen, etc.) into substances required for normal
body functions.
not the absorbed drug.
o For Example, phenoxybenzamine, a drug given to relieve hypertension
caused by pheochromocytoma, a kind of tumor, is biotransformed into a
metabolite, which is the active agent.
toxic xenobiotics and body wastes are converted into less harmful
substances and substances that can be excreted from the body.
STEP 5: Key Points (10 minutes).
converts non-polar or lipid soluble compounds to polar or lipid insoluble
compounds.
readily excreted renally.
STEP 6: Evaluation (10 minutes).
References
States: W.B. Saunders Co.
Morrison R.T and Boyd R N (1997). Organic Chemistry (6th Ed.). New Delhi,
India: Prentice Hall of India
Graham Solomon et al (2014). Organic Chemistry (11th Ed.). New Jeysey,
United States: John Willey and Sons.
Nadendla R. R. (2005). Principles of Pharmaceutical Organic Chemistry. New
Delhi, India: MacMillan Publishers
Bruice Y (2013). Organic Chemistry (7th ed.). New York, United States:
Prentice Hall Pearson.
Delgado J. N. Et al (1998). Wilson and Gisvold's Textbook of Organic
Medicinal and Pharmaceutical Chemistry (10th Ed.). California, United
States: Lippincott Williams
Bhassin S.K, Gupta R.(2013). Pharmaceutical organic chemistry (E-book
Kindle edition). New Delhi, India: Elsevier Publishing Services
———————–
| |
PST 05106 Pharmaceutical Organic Chemistry
NTA Level 5 Semester 1
December 2018
Z
N
Unataka kutumiwa notes hizi kupitia WhatsApp?Kwa notes zilizopangiliwa vizuri kwa kusoma offline au PDF, bonyeza kitufe hapa chini. Ujumbe wenye Level, Semester, Module na Topic utaandaliwa moja kwa moja.TUMIWA NOTES WHATSAPP
