This document discusses drug metabolism and the role of cytochrome P450 enzymes (CYPs). It notes that CYPs are responsible for the majority of drug oxidations in the liver and some extrahepatic tissues. The CYP system uses oxygen and nicotinamide adenine dinucleotide phosphate to metabolize many drugs to more polar, excretable metabolites. CYP3A4 is particularly important as it metabolizes a wide range of drugs. Factors like genetics, age, sex, and coadministered drugs can influence CYP expression and activity levels.
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biotransformation of drug
Biotransformation/Xenobiotic metabolism/ drug metabolism/detoxification.
-Xenobiotics: a wide variety of foreign compounds to which humans get exposed in day to day life.
-It includes unknown compounds, drugs, environmental pollutants, toxins.
-Many xenobiotics can evoke biological responses.
DEFINITION
The biochemical alteration of drug or xenobiotic in the presence of various enzymes that acts as a catalyst which themselves not consumed in the reaction and there by may activate or deactivate the drug is called biotransformation.
Why Biotransformation is necessary?:
To easily eliminate the drug
To terminate drug action by inactivating it
Consequences of Biotransformation
Active to Inactive:
Phenobarbitone---- Hydroxyphenobarbitone
Inactive (prodrug) to Active :
L-Dopa ---- Dopamine
Parathion -- Paraoxon
Talampicillin -- Ampicillin
Active to equally active:
Diazepam -- Oxazepam
Amitriptyline -- Nortriptyline
Imipramine -- Des-imipramine
Codeine -- Morphine
Sites of biotransformation
In the body: Liver, small and large intestines, lungs, skin, kidney, nasal mucosa & brain.
Liver is considered “metabolite clearing house” for both endogenous substances and xenobiotics.
Intestines are considered “initial site of drug metabolism”.
FIRST PASS METABOLISM:
First pass metabolism or presystemic
metabolism or ‘first pass effect’
After oral administeration many drugs are absorbed from the small intestine - transported first via portal system to the liver, where they undergo extensive metabolism before reaching systemic circulation.
fundamental concepts in drug biotransformation
Lipid soluble drugs are poorly excreted in the urine. They tend to store in fat and/or circulate until they are converted (phase I biotransformation) to more water soluble metabolites or metabolites that conjugate (phase II biotransformation) with water soluble substances.
Water soluble drugs are more readily excreted in the urine. They may be metabolized, but generally not by the CYP enzyme systems.
Enzymes catalyzing phase I biotransformation reactions
Enzymes catalyzing phase I biotransformation reactions include:
cytochrome P-450
aldehyde and alcohol dehydrogenase
deaminases
esterases
amidases
epoxide hydratases
Addition of water
Cleavage of R-O or R-N bond accompanied by addition of H2O
CYTOCHROME P450
The cytochrome P-450 families are referred to using an arabic numeral, e.g., CYP1, CYP2, etc.
Each family has a number of subfamilies denoted by an upper case letter, e.g., CYP2A, CYP2B, etc.
The individual enzymes within each subfamily are denoted by another arabic numeral, e.g., CYP3A1, CYP3A2, etc.
Phase I Vs Phase II Drug metabolism and factors affectiing drug metabolism.
Enzyme induction, Enzyme inhibitor, physicochemical properties wthich acan affect the drug metabolism
Definition
History
role of biotransformation
where drug biotransformation occur
the pathway of drug metabolism
phase 2 reaction
plasma level time curve of mephenytoin
factors affecting drug metabolism
importance of biotransformation
metabolism of xenobiotis, drugs, medicine, carcinogen generation by enzymes like cyt p450 mono oxigenases, prostaglandin synthase ect. alcohol metabolism, toxin metabolism, definition of genobiotics, biotransformation, detoxification. effects on health
Drug metabolism /certified fixed orthodontic courses by Indian dental academy Indian dental academy
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and offering a wide range of dental certified courses in different formats.
biotransformation of drug
Biotransformation/Xenobiotic metabolism/ drug metabolism/detoxification.
-Xenobiotics: a wide variety of foreign compounds to which humans get exposed in day to day life.
-It includes unknown compounds, drugs, environmental pollutants, toxins.
-Many xenobiotics can evoke biological responses.
DEFINITION
The biochemical alteration of drug or xenobiotic in the presence of various enzymes that acts as a catalyst which themselves not consumed in the reaction and there by may activate or deactivate the drug is called biotransformation.
Why Biotransformation is necessary?:
To easily eliminate the drug
To terminate drug action by inactivating it
Consequences of Biotransformation
Active to Inactive:
Phenobarbitone---- Hydroxyphenobarbitone
Inactive (prodrug) to Active :
L-Dopa ---- Dopamine
Parathion -- Paraoxon
Talampicillin -- Ampicillin
Active to equally active:
Diazepam -- Oxazepam
Amitriptyline -- Nortriptyline
Imipramine -- Des-imipramine
Codeine -- Morphine
Sites of biotransformation
In the body: Liver, small and large intestines, lungs, skin, kidney, nasal mucosa & brain.
Liver is considered “metabolite clearing house” for both endogenous substances and xenobiotics.
Intestines are considered “initial site of drug metabolism”.
FIRST PASS METABOLISM:
First pass metabolism or presystemic
metabolism or ‘first pass effect’
After oral administeration many drugs are absorbed from the small intestine - transported first via portal system to the liver, where they undergo extensive metabolism before reaching systemic circulation.
fundamental concepts in drug biotransformation
Lipid soluble drugs are poorly excreted in the urine. They tend to store in fat and/or circulate until they are converted (phase I biotransformation) to more water soluble metabolites or metabolites that conjugate (phase II biotransformation) with water soluble substances.
Water soluble drugs are more readily excreted in the urine. They may be metabolized, but generally not by the CYP enzyme systems.
Enzymes catalyzing phase I biotransformation reactions
Enzymes catalyzing phase I biotransformation reactions include:
cytochrome P-450
aldehyde and alcohol dehydrogenase
deaminases
esterases
amidases
epoxide hydratases
Addition of water
Cleavage of R-O or R-N bond accompanied by addition of H2O
CYTOCHROME P450
The cytochrome P-450 families are referred to using an arabic numeral, e.g., CYP1, CYP2, etc.
Each family has a number of subfamilies denoted by an upper case letter, e.g., CYP2A, CYP2B, etc.
The individual enzymes within each subfamily are denoted by another arabic numeral, e.g., CYP3A1, CYP3A2, etc.
Phase I Vs Phase II Drug metabolism and factors affectiing drug metabolism.
Enzyme induction, Enzyme inhibitor, physicochemical properties wthich acan affect the drug metabolism
Definition
History
role of biotransformation
where drug biotransformation occur
the pathway of drug metabolism
phase 2 reaction
plasma level time curve of mephenytoin
factors affecting drug metabolism
importance of biotransformation
metabolism of xenobiotis, drugs, medicine, carcinogen generation by enzymes like cyt p450 mono oxigenases, prostaglandin synthase ect. alcohol metabolism, toxin metabolism, definition of genobiotics, biotransformation, detoxification. effects on health
Pharmacokinetics involves absorption, distribution, metabolism and excretion. Metabolism involves a huge range of chemical reactions which occur at body temperature with the help of enzymes
pharmacokinetics- action of body on the drug. includes absorption, dissolution, metabolism and excretion of drug. In this presentation metabolism and excretion of the drug are covered . Includes conversion of lipophilic / non-water soluble compounds into easily removable compounds by the action of hepatic enzymes which can be microsomal or non-microsomal . Excretion is further removal or elimination of compounds or agents from the body. Drug elimination is the sum of the processes of removing an administered drug from the body. In the pharmacokinetic ADME scheme (absorption, distribution, metabolism, and excretion), it is frequently considered to encompass both metabolism and excretion. Hydrophobic drugs, to be excreted, must undergo metabolic modification making them more polar. Hydrophilic drugs, on the other hand, can undergo excretion directly, without the need for metabolic changes to their molecular structures. Introduction
Most drugs are xenobiotics, ie, chemical substances not naturally produced by the body. Xenobiotics undergo various body processes for detoxification, thus reducing their toxicity and allowing them to be readily available for excretion. These processes allow for the chemical modification of drugs into their metabolites and are known as drug metabolism or metabolic biotransformation.
These metabolites are the byproducts of drug metabolism and can be characterized by active, inactive, and toxic metabolites. Active metabolites are biochemically active compounds with therapeutic effects, whereas inactive metabolites are biochemically inactive compounds with neither a therapeutic nor toxic effect. Toxic metabolites are biochemically active compounds similar to active metabolites but have various harmful effects.
Drug metabolism occurs at a specific location in the body, resulting in a low concentration of active metabolites in the systemic circulation. This phenomenon is called first-pass metabolism because it limits drug bioavailability. First-pass metabolism primarily occurs in the liver; however, metabolizing enzymes can be found throughout the body.
Understanding these alterations in chemical activity is crucial in utilizing the optimal pharmacological intervention for any patient. This is a topic of interest to any provider who routinely treats patients with medications. The metabolism of pharmaceutical drugs is an important aspect of pharmacology and medicine. For example, the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Drug metabolism also affects multidrug resistance in infectious diseases and in chemotherapy for cancer, and the actions of some drugs as substrates or inhibitors of enzymes involved in xenobiotic metabolism are a common reason for hazardous drug interactions. These pathways are also important in environmental science, with the xenobiotic metabolism of microorganisms determining whether a pollutant will be broken down or not is covered.pharmacokinetic
1. Introduction
2. Phases of metabolism
3. Phase-I Metabolism
4. Cytochrome P family
5. Phase –II Metabolism
6. First pass metabolism
7. Ante Drugs
8. Microsomal Enzymes induction
Role of metabolism in drug discovery
This is a set of powerpoint slides with self-assessment questions interspersed throuought on drug metabolism and pharmacogenetics. The aim is to understand the mechanism of clinically significant drug interactions, recognize potentially clinically significant genetic influences on drug efficacy and toxicity, and genetic predispositions to disease due to altered drug metabolism or transport. This resource is appropriate for medical students or graduate healthcare professionals such as nursing students.
Genetic polymorphisms are variations in gene sequences that occur in at least 1% of the general population, resulting in multiple alleles or variants of a gene sequence.
The most commonly occurring form of genetic variability is the single nucleotide polymorphism (SNP, often called “snip”)
Instructions for Submissions thorugh G- Classroom.pptxJheel Barad
This presentation provides a briefing on how to upload submissions and documents in Google Classroom. It was prepared as part of an orientation for new Sainik School in-service teacher trainees. As a training officer, my goal is to ensure that you are comfortable and proficient with this essential tool for managing assignments and fostering student engagement.
Model Attribute Check Company Auto PropertyCeline George
In Odoo, the multi-company feature allows you to manage multiple companies within a single Odoo database instance. Each company can have its own configurations while still sharing common resources such as products, customers, and suppliers.
Palestine last event orientationfvgnh .pptxRaedMohamed3
An EFL lesson about the current events in Palestine. It is intended to be for intermediate students who wish to increase their listening skills through a short lesson in power point.
Students, digital devices and success - Andreas Schleicher - 27 May 2024..pptxEduSkills OECD
Andreas Schleicher presents at the OECD webinar ‘Digital devices in schools: detrimental distraction or secret to success?’ on 27 May 2024. The presentation was based on findings from PISA 2022 results and the webinar helped launch the PISA in Focus ‘Managing screen time: How to protect and equip students against distraction’ https://www.oecd-ilibrary.org/education/managing-screen-time_7c225af4-en and the OECD Education Policy Perspective ‘Students, digital devices and success’ can be found here - https://oe.cd/il/5yV
How to Make a Field invisible in Odoo 17Celine George
It is possible to hide or invisible some fields in odoo. Commonly using “invisible” attribute in the field definition to invisible the fields. This slide will show how to make a field invisible in odoo 17.
How to Create Map Views in the Odoo 17 ERPCeline George
The map views are useful for providing a geographical representation of data. They allow users to visualize and analyze the data in a more intuitive manner.
Unit 8 - Information and Communication Technology (Paper I).pdfThiyagu K
This slides describes the basic concepts of ICT, basics of Email, Emerging Technology and Digital Initiatives in Education. This presentations aligns with the UGC Paper I syllabus.
Operation “Blue Star” is the only event in the history of Independent India where the state went into war with its own people. Even after about 40 years it is not clear if it was culmination of states anger over people of the region, a political game of power or start of dictatorial chapter in the democratic setup.
The people of Punjab felt alienated from main stream due to denial of their just demands during a long democratic struggle since independence. As it happen all over the word, it led to militant struggle with great loss of lives of military, police and civilian personnel. Killing of Indira Gandhi and massacre of innocent Sikhs in Delhi and other India cities was also associated with this movement.
Ethnobotany and Ethnopharmacology:
Ethnobotany in herbal drug evaluation,
Impact of Ethnobotany in traditional medicine,
New development in herbals,
Bio-prospecting tools for drug discovery,
Role of Ethnopharmacology in drug evaluation,
Reverse Pharmacology.
3. liver MicrosoMal systeM
Oxidative Reactions: Cytochrome P450 mediated
Examples
Formation of an inactive polar metabolite
• Phenobarbital
Formation of an active metabolite
• By Design: Purine & pyrimidine chemotherapy
prodrugs
• Inadvertent: terfenadine – fexofenadine
Formation of a toxic metabolite
• Acetaminophen – NAPQI
4. cytochroMe P450 isoforMs
(cyPs) - an overview
• NADPH + H+
+ O2 + Drug → NADP+
+ H2O + Oxidized Drug
• Carbon monoxide binds to the reduced Fe(II) heme and absorbs
at 450 nm (origin of enzyme family name)
• CYP monooxygenase enzyme family is major catalyst of drug
and endogenous compound oxidations in liver, kidney, G.I. tract,
skin, lungs
• Oxidative reactions require the CYP heme protein, the
reductase, NADPH, phosphatidylcholine and molecular oxygen
• CYPs are in smooth endoplasmic reticulum in close association
with NADPH-CYP reductase in 10/1 ratio
• The reductase serves as the electron source for the oxidative
reaction cycle
5. cyP faMilies
• Multiple CYP gene families have been identified in
humans, and the categories are based upon protein
sequence homology.
• Most of the drug metabolizing enzymes are in
CYP 1, 2, & 3 families.
• CYPs have molecular weights of 45-60 kDa.
• Frequently, two or more enzymes can catalyze the
same type of oxidation, indicating redundant and
broad substrate specificity.
• CYP3A4 is very common to the metabolism of many
drugs; its presence in the GI tract is responsible for
poor oral availability of many drugs.
6. CYP NomeNClature
• Families - CYP plus arabic numeral (>40%
homology of amino acid sequence, eg. CYP1)
• Subfamily - 40-55% homology of amino acid
sequence; e.g. CYP1A
• Subfamily - additional arabic numeral when more
than 1 subfamily has been identified; e.g. CYP1A1
• Italics indicate gene (CYP1A2); regular font for
enzyme
• Comprehensive guide to human Cyps
7. CYP tables
• Human CYPs- variability and importance in drug
metabolism
• Isoforms in metabolism of clinically important drugs
• Factors that influence CYP activity
• Non-Nitrogenous CYP inhibitors
• Extrahepatic CYPs
8. RELATIVE HEPATIC CONTENT
OF CYP ENZYMES
% DRUGS METABOLIZED
BY CYP ENZYMES
role oF CYP eNZYmes IN
HePatIC DruG metabolIsm
9. HumaN lIver DruG CYPs
CYP
enzyme
Level
(%total)
Extent of
variability
1A2 ~ 13 ~40-fold
1B1 <1
2A6 ~4 ~30- 100-fold
2B6 <1 ~50-fold
2C ~18 25-100-fold
2D6 Up to 2.5 >1000-fold
2E1 Up to 7 ~20-fold
2F1
2J2
3A4 Up to 28
30-60*
~20-fold
90-fold*
4A, 4B2E
10. PartICIPatIoN oF tHe CYP eNZYmes IN
metabolIsm oF some ClINICallY
ImPortaNt DruGs
CYP Enzyme Examples of substrates
1A1 Caffeine, Testosterone, R-Warfarin
1A2 Acetaminophen, Caffeine, Phenacetin, R-Warfarin
2A6 17β-Estradiol, Testosterone
2B6 Cyclophosphamide, Erythromycin, Testosterone
2C-family Acetaminophen, Tolbutamide (2C9); Hexobarbital, S-
Warfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin,
Zidovudine (2C8,9,19);
2E1 Acetaminophen, Caffeine, Chlorzoxazone, Halothane
2D6 Acetaminophen, Codeine, Debrisoquine
3A4 Acetaminophen, Caffeine, Carbamazepine, Codeine,
Cortisol, Erythromycin, Cyclophosphamide, S- and R-
Warfarin, Phenytoin, Testosterone, Halothane,
Zidovudine
11. Red indicates enzymes important in drug metabolism
Factors InFluencIng actIvIty and
level oF cyP enzymes
Nutrition
1A1;1A2; 1B1, 2A6, 2B6,
2C8,9,19; 2D6, 3A4,5
Smoking 1A1;1A2, 2E1
Alcohol 2E1
Drugs
1A1,1A2; 2A6; 2B6; 2C;
2D6; 3A3, 3A4,5
Environment
1A1,1A2; 2A6; 1B; 2E1;
3A3, 3A4,5
Genetic
Polymorphism
1A; 2A6; 2C9,19; 2D6;
2E1
12. non-nItrogenous substances that
aFFect drug metabolIsm
• Grapefruit juice - CYP 3A4 inhibitor; highly
variable effects; fucocoumarins
– Bailey, D.G. et al.; Br J Clin Pharmacol 1998,
46:101-110
– Bailey, D.G et al.; Am J Cardiovasc Drugs 2004,
4:281-97.
• St John’s wort, other herbal products
– Tirona, R.G and Bailey, D.G. ; Br J Clin
Pharmacol. 2006,61: 677-81
• Isosafrole, safrole
– CYP1A1, CYP1A2 inhibitor; found in root beer,
perfume
14. human drug metabolIzIng cyPs
located In extrahePatIc tIssues
CYP
Enzyme
Tissue
2E1 Lung, placenta, others
2F1 Lung, placenta
2J2 Heart
3A
GI tract, lung, placenta, fetus, uterus,
kidney
4B1 Lung, placenta
4A11 Kidney
15. cyP bIotransFormatIons
• Chemically diverse small molecules are
converted, generally to more polar compounds
• Reactions include (see text):
– Aliphatic hydroxylation, aromatic hydroxylation
– Dealkylation (N-,O-, S-)
– N-oxidation, S-oxidation
– Deamination
– Dehalogenation
16. NoN-CYP drug oxidatioNs (1)
• Monoamine Oxidase (MAO), Diamine Oxidase (DAO) -
MAO (mitochondrial) oxidatively deaminates
endogenous substrates including neurotransmitters
(dopamine, serotonin, norepinephrine, epinephrine);
drugs designed to inhibit MAO used to affect balance
of CNS neurotransmitters (L-DOPA); MPTP converted
to toxin MPP+ through MAO-B. DAO substrates
include histamine and polyamines.
• Alcohol & Aldehyde Dehydrogenase - non-specific
enzymes found in soluble fraction of liver; ethanol
metabolism
• Xanthine Oxidase - converts hypoxanthine to
xanthine, and then to uric acid. Drug substrates
include theophylline, 6-mercaptopurine. Allopurinol is
substrate and inhibitor of xanthine oxidase; delays
metabolism of other substrates; effective for
treatment of gout.
17. • Flavin Monooxygenases
– Family of enzymes that catalyze oxygenation of nitrogen,
phosphorus, sulfur – particularly facile formation of N-oxides
– Different FMO isoforms have been isolated from liver, lung (S.K.
Krueger, et al. Drug Metab Rev 2002; 34:523-32)
– Complete structures defined (Review: J. Cashman, 1995, Chem Res
Toxicol 8:165-181; Pharmacogenomics 2002; 3:325-39)
– Require molecular oxygen, NADPH, flavin adenosine dinucleotide
(FAD)
– Single point (loose) enzyme-substrate contact with reactive
hydroperoxyflavin monoxoygenating agent
– FMOs are heat labile and metal-free, unlike CYPs
– Factors affecting FMOs (diet, drugs, sex) not as highly studied as
CYPs
NoN-CYP drug oxidatioNs (2)
18. drug MetabolisM - WWW
iNforMatioN resourCes
•http://www.icgeb.trieste.it/p450/
– Directory of P450 Containing Systems; comprehensive web
site regarding all aspects of chemical structure (sequence
and 3D) of P450 proteins from all species; steroid ligands;
links to related sites including leading researchers on P450
•http://www.fda.gov/cder/guidance/
– Site contains many useful documents regarding drug
metabolism and FDA recommendations including "Drug
Metabolism/Drug Interaction Studies in the Drug Development
Process: Studies in Vitro", FDA Guidance for Industry
•http://www.sigmaaldrich.com/Area_of_Interest/Biochem
icals/Enzyme_Explorer.html
– Site has many commercially available drug metabolizing
enzymes and useful links to multiple drug metabolism
resources
