drug metabolism (...
TRANSCRIPT
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