MOLECULAR PHARMACOLOGY 5.

Combinatorial Synthesis – OTC drugs such as

- Programs that focuses on scientific study of neozep, decolgen.
biochemical and biophysical characteristics of drugs
at molecular level, interaction with the effects on DRUG DISCOVERY
biological macromolecules and cellular structures and  Molecular Modification
processes.  Mechanism-based Design
- Computer-aided Design
SOURCES OF NEW DRUGS - Serendipity and Prepared Mind
 PLANT KINGDOM  Use of NMR
o Digitalis lanata – Digoxin (Heart Failure)
IDENTIFYING A BIOASSAY
o Morphine – Papaver somniferum (Analgesic) 1. In Vitro Test
 ANIMAL SOURCES - Initial bioassay that takes place outside the organism,
o Draculin – Saliva of vampire bat – MI of (Heart in an artificial environment such as a laboratory where
Attack) drug activity is tested on isolated tissues, cells, or
o Urine of pregnant Mare – Hormone enzymes.
o COD Liver – Gadus morhua: Sodium Morrhuate –
Anti-varicose 2. In Vivo Test
 MICROBIOLOGICAL WORLD - Subsequent bioassay by biological experiment or
o Antibiotics - Penicillin technique carried out within a living organism.
 BIOLOGICAL SOURCE
o (Vaccine, Serum, Biologics)
STEP BY STEP IN DRUG DISCOVERY
DRUG DISCOVERY FACTORS: 1. New Chemical Entity – organic synthesis, molecular
1. Choosing a Disease – Focus is on the financial return modification study
2. Preclinical – chemistry, physical and chemical
2. Choosing a Drug Target – Receptor, enzymes, and property, biological, pre-formulation, pharmacology,
metabolic processes. toxicology, kinetics and dynamics, bioassay
 Olol – Propranolol, Atenolol, Metoprolol (Beta 1 3. Investigational New Drug Application (INDA) – FDA
Antagonist) approx. 1 YEAR
 Beta 1 – 4. Clinical Trial
o Normal Agonist > Vasoconstriction (HTN)  Phase I – metabolic and pharmacological actions.
o Antagonist > Vasodilation - Evaluates drug metabolism, structure activity
 Allopurinol (Purinase) relationships, and the mechanism of action in
MOA: Inh. Xanthine oxidase enyzyme humans.
o Hypoxanthine > (X.O) > Xanthine > (X.O) > Uric  Phase II – determine the common short term side
acid (Gout) effects and risk associated with the drug.
 Statins (Atorvastatin, Rosuvastatin, Simvastatin) - Failure during phase II is common.
o Inhibits HMG-coA Reductase Inh. - After phase 2, sponsors meet with FDA.
 Mevalonic acid – rate limiting step in coversion of  Phase III – intended to gather the additional
cholesterol. information about effectiveness and safety that is
needed to evaluate the overall benefit-risk relationship
3. Medical Folklore of the drug.
o 10 Halamang Gamot - Also provides adequate basis for extrapolating the
results to the general population and transmitting that
4. Existing Drugs information in the physician labeling.
o Burimamide (poor bioavailability) > Metiamide 5. New Drug Application (NDA) – FDA – 1.5 YEARS
(Agranulocytosis) > Cimetidine (H2 Receptor (Action)
Antagonist) 6. Phase IV (Post Marketing Surveillance) - modification
o Dicholoroisoproterenol on drug formulation as obtained from manufccturing
(partial sympathomimetic act.) > Pronethanol (ADE: scale-up and validation.
Light headedness) > Propranolol (Non-selective
B1/B2 antagonist) – Asthma = 15 YRS – 20 YRS.

PRE – CLINICAL STUDIES

  PHARMACOLOGY – the science of the properties of  Change in formulation, analytical standards, method
the drugs and its effects in the body. of manufacture, or in-process control of the drug
 PHARMACODYNAMICS – the study of the interaction product.
of drugs with cells. (What the drug does to the body)  Change in the container and closure system for a
 PHARMACOKINETICS – handling of a drug within drug product.
the body, includes ADME process. (What the body  Extension of the exp date for a drug product based on
does to the drug) new stability data.
 TOXICITY TESTING – In vitro and in vivo testing; LEAD COMPOUND – a prototype chem compound that has a
determination of LD 50. (Dose that cause fatality in fundamental desired biologic or pharmacologic activity.
50% population) FINASTERIDE (Proscar) – Benign Prostatic Hyperplasia (BPH)
 PHARMACEUTICS – general area of study Finasteride (Propecia) – Male pattern baldness.
concerned with the formulation, manufacturing A/E: Hirsutism, bronchoconstriction
stability and effectiveness of a pharmaceutical dosage PRODRUGS – compound that requires metabolic
form. biotransformation after administration to produce the desired
INVESTIGATIONAL NEW DRUG APPLICATION pharmacologically active compound.
- Filed before drug may be given to human (clinical Ex: Enalapril (ACE Inh) ---- (Hydrolysis) > Enalaprilat (Active
trials) metabolite)
ORPHAN DRUG – treat orphan disease or disease that NEW DRUG
affects fewer than 200,000 people in the US - combination of two or more old drugs or change in
- Submitted to FDA  Reviewed by FDA for 30 days usual proportions of drugs in an established
1.2 Carry out Clinical Trial combination product is considered new if the change
PHAS NO.OF PURPOSE % alter safety and efficacy.
E PATIENT SUCCESSFULL - Change in previously approved formulation or method
S Y COMPLETING of manufacture constitutes newness since such
I 20-80 Healthy Safety 67 change can alter effects and safety of a product.
Voluntee - Proposed new use for an established drug.
r
II 100-300 Suffer Safety and 45 PHYSICOCHEMICAL PROPERTIES
from effectivenes ACID BASE
target s Taste Sour Bitter
illness
Litmus Paper Blue to Red Red to Blue
III 1000- With the Safety, 5-10
3000 target effectivenes Methyl Orange Red Yellow
illness s and Phenolphthalein Colorless Pink/Red
dosage
Corrosive Not all are
Corrosive
ANDA or Abbreviated New Drug Application
- Filed for generic copies by competing companies Aqueous Solution H+ upon OH- upon
following expiration of patent term protection. contact contact
Branded – conduct clinical trial
Generic – copycat; cheaper than branded
BIOLOGICS LICENSE APPLICATION (BLA)  ARRHENIUS THEORY – Svante Arrhenius
- For the manufacture of biological products, vaccines Acid – Dissociation of H+ in aqueous solution
and toxins. H+ + H20 -> H3O (Hydronium)
ANIMAL DRUG APPLICATIONS Base – Dissociation of OH- in aqueous solution
- Specific regulation pertaining to the approval for the NaOH >< Na+ + OH-
marketing and labeling of drugs intended for animal Limitation: H2SO4 / HCl + toluene (Acid)
use. NaNH2 + NH3 (Base)
- Regulation apply: INADA’s NADA’s, SNADA’s and
abbreviated NADA’s  BRONSTED – LOWRY THEORY
SUPPLEMENTAL NEW DRUG APPLICATION (SNDA) - Johannes Nicolaus Bronsted & Martin Lowry
- Changes in synthesis, formulation, analytical Acid – Proton (H+) donor
standards, containers, and labeling of drug products. Base – Proton (H+) acceptor
 Change in the method of synthesis of the drug HA + B >< HB+ + A-
substance Acid Base Conjugate acid Conjugate base
Conjugate acid – base that receive proton
Conjugate base – acid that donates a proton B. Solubility
NH3 + H2O >< NH4 + OH- - the amount of ml in water capable of dissolving one gram of a
Base Acid C.A C.B given substance.
HCl + H20 >< H3O + Cl- Solubility Factor
Acid Base C.A + C.B Very Soluble <1mL
Amphiprotic – serve as both acid/base Freely Soluble 1-10
Soluble 10-30
 LEWIS THEORY – Gilbert Lewis Sparingly Soluble 30-100
Acid – compound that receive an electron pair Slightly Sol 100-1K
Base – compound that donates an electron pair Very Slightly Sol 1K -10K
Practically Sol. / Insoluble >10K
ACID STRENGTH – refers to its ability or tendency to lose a
proton (H+) Some basic properties of water
STRONG Ionizes HCl, HI, HBr, a. Bond angles
ACID (dissociates) in HClO4, b. Charge distribution
a solution HNO3+ c. H-Bonding
H2SO4 VSEPR – Valence Shell Electron Pair Repulsion Theory
WEAK ACID Partially H2CO2 Model to predict the geometry of an individual
dissociates CH3COOH molecule
So I Brought No Clean Clothes – Sulfuric, Iodic, Boric, Hydrogen bonding – dipole – dipole bond
Nitric, Hydrochloric, C. DRUG POLARITY
Perchloric Acid - it is a relative measure of a drug’s lipid and water solubility
Acid dissociation constant (Ka) – strength of an acidic and is usually expressed in terms of a partition coefficient.
molecule Partition Coefficient – ratio of conc of compounds in mixture of
Stronger acid = Larger dissociation constant 2 immiscible solvents.
( (Ka) - Water – octanol partition coefficient
Smaller logarithmic constant (pka) Water aq .
Log P = [ ]
pH – aqueous acid solution Octanol
Water Solubility (Hydrophilicity) – depends primarily on two
Ionization for acids and bases factors:
 Weakly acidic drugs are less ionized in acid media 1. Ionic character POLAR
than alkaline media 2. Hydrogen – bonding capabilities
 PKa of acidic drug > pH of medium = more than 50% The presence of oxygen and nitrogen containing functional
in its non-ionized (molecular) form. = more likely to groups usually enhances water solubility.
cross lipid cellular membranes.
Organic acids contain one or more functional groups: Water solubility is required to:
(1) Carboxylic acid group (-COOH) 1. Dissolution in the GI track
(2) Phenolic group 2. Preparation of parenteral solutions (as opposed to
(3) Sulfonic acid group suspensions)
(4) Sulfonamide group 3. Preparation of ophthalmic solutions
(5) Imide group 4. Adequate urine concentrations (antibiotics)
(6) Beta-carbonyl group
Strong inorganic bases Lipid solubility (lipophilicity) is enchanced by nonionizable
 Sodium hydroxide hydrocarbon chains and ring systems
 Potassium hydroxide Lipid solubility is required for:
 Magnesium hydroxide 1. Penetration through the lipid bilayer in the GI tract
 Calcium hydroxide ABSORPTION
 Barium hydroxide 2. Penetration through the blood brain barrier
3. Preparation of intramuscular (IM) depot injectable
 Quaternary ammonium hydroxides
formulations.
- Completely ionized
Drugs in SALT Form
Organic bases contain the following functional group
(1) Primary, secondary or tertiary aliphatic or alicyclic  A salt is the combination of an acid and a base.
amino group  Two classes based upon the chemical nature of the
(2) Most aromatic or unsaturated heterocyclic nitrogen substance
 Inorganic salts – combining drug molecules with inorganic
A. Acids and Bases acids and bases.
  Increased water solubility in comparison with the  OCCUPATIONAL THEORY OF RESPONSE
parent molecule. - Intensity of pharmacologic activity of a structurally
 Organic salts – combining two drug molecules, one acidic specific drug is directly proportional to the number of
and one basic. receptors occupied by the drug.
 Increased lipid solubility – generally is used to make AFFINITY – how strongly a drug binds to a receptor
depot injections. EFFICACY – max biological effect resulting from a drug
binding to its target.
LIPINSKI’S RULE OF FIVE (Christopher Lipinski) ENZYME – protein catalysts produced by living cells by acting
 Pfizer’s rule of five or rule of five (RO5) as a surface or focus for the reaction, bringing the substrates
- Most of orally administered drugs. together and holding them in the best position for the reaction.
 Solubility TYPE OF RECEPTOR ACTION
 Permeability DOWN – REGULATION – caused by continuous prolonged
 Plasma binding exposure of receptors to drugs that disrupt the homeostatic
 Absorption equilibrium and result in altered levels of receptors.
Rule:  Up regulation – receptor is high, low drug
MW: <500 g/mol  Down regulation – low receptor, high drug
Hydrogen Bond Donor: <5 (OH + NH) - disruption involves endocytosis of ligand-bound receptors,
Hydrogen Bond Acceptor: <10 (O,N) resulting in:
Partition Coefficient: +5 * sequestration of receptors from the cell surface
- Rule of thumb to evaluate druglikeness or determine if * accelerated degradation of the receptors,
a chemical compound with a certain pharmacological * or inactivation of the receptors.
or biological activity has chemical properties and
physical properties that would make it a likely orally DESENSITIZATION
active drug in humans. - Result of down regulation
- No more than 5 hydrogen bond donors (total number - Target cells become desensitized and the effect of
of nitrogen-hydrogen and oxygen-hydrogen bonds) subsequent exposure to the same concentration of
- No more than 10 hydrogen bond acceptors (all the drug is reduced.
nitrogen or oxygen atoms) - Is there a need to adjust the dose of the drug?
- A molecular mass less than 500 daltons. - Tolerance - high dose , high toxicity
- An octanol-water partition coefficient (logP) that does - Increased conc of the drug is required to produce a
not exceed 5 effect of the same magnitude as the initial exposure
 Omeprazole is a popular drug that conforms to with a smaller drug conc.
Lipinski’s rule of 5.
PHARMACODYNAMIC
- Drug actions – dynamic interactions between drug
molecules and cellular components.
Types of molecules that a drug may act upon:
 Lipid – Amphotericin B
 Carbohydrate – molecular tag
 Protein – receptors
 Nucleic acids target – DNA and RNA acting as drug
RECEPTOR – cell or group of cells specialized to defect
changes in the environment and trigger impulses in the
sensory nervous system
- Protein in nature and embedded in the cell membrane
Ligand – molecule that binds to a receptor
Peptide (short protein) – Ex: neurotransmitter, hormone, drugs,
toxins
THEORIES DESCRIBING THE PHARMACOLOGIC ACTIVITY
OF THE DRUG:
 LOCK AND KEY THEORY
- Completely complementary relationship between the
drug molecule and a specific area on the surface of
the receptor molecule.
 INDUCED FIT THEORY
- Drug molecule and its active site
.PHARMACEUTICAL AND (b) Numerous functional groups that can combine
enzymatically with glucuronic acid
MEDICINAL ORGANIC (c) The glucuronyl moiety (with its ionized
CHEMISTRY carboxylate (pKa 3.2) and polar hydroxyl
PMOC311/ LECTURE/ WEEK 5 groups)which, when attached to xenobiotic
substrates, greatly increases the water solubility of
the conjugated product.
PHASE 2 METABOLISM
TWO STEPS IN THE FORMATION OF B –GLUCURONIDES
PHASE II OR CONJUGATION REACTIONS
 Involves synthesis of an activated coenzyme,
 Attachment of small, polar and ionizable
uridine-5'-diphospho-a-D-glucuronic acid (UDPGA)
endogenous molecules that are ready for excretion,
 Subsequent transfer of the glucuronyl group from
such as:
UDPGA to an appropriate substrate
o Glucuronic acid - Polar o catalyzed by microsomal enzymes called
o Sulfate
UDP-glucuronyltransferases
o Glycine - H20 Soluble
 Found primarily in the liver but also
o Glutamine occur in kidneys, intestine, skin,
 Acetylation and Methylation don’t provide polar lungs, and brain.
compounds. They make the substance detoxify and  UTP - Uridylyl transferase
attenuating or decrease their pharmacological
activity

CONJUGATED PRODUCTS
 Relatively water soluble and readily excretable
 Biologically inactive and nontoxic
 METHYLATION AND ACETYLATION
o Do not generally increase water solubility
but mainly serve to terminate or attenuate
pharmacological activity
 Phase II reactions can be regarded as detoxifying
pathways
 The role of Glutaryl L-cysteinyl glycine (GSH) is to
combine with chemically reactive compounds to
prevent damage to important biomacromolecules
such as DNA, RNA and proteins.

PHASE 2
 Endogenous compounds that undergo conjugation
reactions
o Bilirubin
o Steroids
o Catecholamines (NE, E, D) - Methylation
o Histamine
 Mediated by more specific transferase enzymes.

GLUCURONIC ACID CONJUGATION

 The most common conjugative pathway in drug TYPES OF COMPOUNDS FORMING OXYGEN.
metabolism for several reasons: NITROGEN, SULFUR, AND CARBON GLUCURONIDE
(a) A readily available supply of D-glucuronic acid
(predomonantly in the pathway) OXYGEN GLUCURONIDES
i. D-glucoronic acid is the derivative of HYDROXYL COMPOUNDS
glucose whicj are highly soluble product  Phenols: Morphine, Acetaminophen. P-
 hydroxyphenytoin (metabolite of Phenytoin)

 Alcohols: Tricholoroethanol. Chloramphenicol.

Propranolol

 Enols: 4-hydroxycoumarin

 N-Hydroxyamines: N-Hydroxydapsone

 N-Hydroxyamides: N-Hydroxy-2-acetylaminofluorene
GLUCURONIC ACID CONJUGATION
CARBOXYL COMPOUNDS
 Aryl acids: Benzoic acid, Salicylic acid Glycine
conjuga
tion
 Arylalkyl acids: Naproxen. Fenoprofen

GLUCURONIC ACID CONJUGATION

 Functional groups undergoing glucuronidation:
Phenolic hydroxyls
 Morphine, Acetaminophen, hydroxyphenytoin

O-GLUCURONIDE

 ENOLS: Eg. 4-hydroxycoumarin

Gl

 N-HYDROXYAMINES: Eg. N-Hydroxydapsone

 N-HYDROXYAMIDES: Eg. N-Hydroxy-2 Gl

acetylaminofluorene

O-GLUCURONIDE CARBOXYL COMPOUNDS

Gl
 ARYL ACIDS: benzoic acid, salicylic acid
 Gl

 ARYLALKYL ACIDS:

Naproxen

Gl
Fenoprofen
S-GLUCURONIDE
SULFUR GLUCURONIDE
 Sulfhydryl groups: methimazole, propylthiouracil,

Gl diethyithiocarbamic acid

N-GLUCURONIDES
NITROGEN GLUCURONIDES
Gl
Arylamines: 7-amino-5-nitroimidazole
Alkylamines: Desipramine
Amides: Meprobamate
Sulfonamides:
Tertiary amines:
Sulfisoxazole
Cyproheptadine, Tripelennamine Gluc
N-GLUCURONIDES
Gl
Gl
C-GLUCURONIDES
CARBON GLUCURONIDES
 3,5-Pyrazolidinedione: phenylbutazone (Butazolidin)

 sulfinpyrazone (Anturane)
 GLUCURONIDATION
 In neonates and children (Sulfation 1st),
glucuronidating processes are often not developed
fully DRUGS SUSCEPTIBLE TO SULFATE FORMATION
  Drugs containing phenolic moieties
accumulation of drug  O-sulfate because SO3 is attaching to Oxygen

toxicity
 NEONATAL HYPERBILIRUBINEMIA
o Inability of newborns to conjugate Bilirubin
with glucuronic acid S
 GRAY BABY SYNDROME
o Inability to metabolize Chloramphenicol S
o Due to Metheglobinemia inability of the red
blood cell to carry oxygen S
SULFATE CONJUGATION  For many phenols, sulfoconjugation may represent
 Endogenous compounds that underogo sulfate only a minor pathway.
conjugation: Phenol, Aromatic amine, N-hydroxy o Competes with Glucuronidation of phenols
compounds  Eg. acetaminophen
 Sulfation is limited in the body
 Steroids, heparin. Chondroitin, catecholamines, and
thyroxine.

SULFATE CONJUGATION PROCESS

 Involves activation of inorganic sulfate to the  In adults:
coenzyme 3'-phosphoadenosine-5'.phosphosulfate o Major metabolite: O-glucuronide conjugate
(PAPS). o O-sulfate conjugate formed in small
 Subsequent transfer of the sulfate group from PAPS amounts
to the accepting substrate is catalyzed by various  In infants and young children (ages 3 to 9 years)
soluble sulfotransferases present in the liver and o O-sulfate conjugate is the main urinary
other tissues (e.g.. Kidneys, intestine). product
 Leads to water-soluble and inactive metabolite.
DRUGS SUSCEPTIBLE TO SULFATE FORMATION
 Alcohols (e.g.. Aliphatic C1 to C5 alcohols,
diethylene glycol
 Aromatic amines
 (e.g.. aniline, 2-naphthylamine)
 O-sulfate conjugates of some N-hydroxy
compounds give rise to toxic metabolites
  Aromatic acids and arylalkyl acids are the major
substrates undergoing glycine conjugation.



Hepatotoxic and nephrotoxic
Sulfate conjugation of N hydroxy metab à 0-sulafte
gyl
esters (ultimate carcinogenic agent)

CONJUGATION WITH GLYCINE,GLUTAMINE AND GLYCINE CONJUGATION

OTHER AMINO ACIDS
 Glycine and Glutamine are used by mammalian
systems to conjugate carboxylic acids, particularly
Aromatic Acids and Arylalkyl Acids

 Not converted to activated co-enzymes

 Instead, the carboxylic acid substrate is activated

with adenosine triphosphate (ATP) and co-
enzymeA (CoA) to form an acyl-CoA complex

 Acylation of glycine or glutamine by N- Isoniazid major conjugation reaction is Acetylation
acyltransferase (Mitochondria Of Liver and Kidney
Cells) GLUTAMINE CONJUGATION
  Arene oxides and aliphatic epoxides (or
oxiranes) represent a very important class of
substrates that are conjugated and detoxified
by GSH.
 Arene oxides: Benzo α-pyrine-4,5-oxide & 4-
bromobenzene oxide
 Alipahatic oxides: Styrene oxide

ACETYLATION
 constitutes an important metabolic route for drugs
containing PRIMARY AMINO GROUPS . Decrease
the pharmacological activity
o Primary Aromatic Amines (ArNH2)
o Sulfonamides (H2NC6H4SO2NHR).
o Hydrazines (—NHNH2)
GSH OR MERCAPTURIC ACID CONJUGATES
o Hydrazides (—CONHNH2)
 Important pathway for detoxifying chemically
o and Primary Aliphatic Amines
reactive electrophilic compounds
 The amide derivatives formed from acetylation of
 GSH protects vital cellular constituents against
these amino functionalities are generally inactive
chemically reactive species by virtue of its
and nontoxic.
nucleophilic sulfhydryl (SH) group.
 primary function of acetylation: is to terminate
 The SH group reacts with electron-deficient
pharmacological activity and detoxification
compounds to form S-substituted GSH adducts
 Few reports indicate that acetylated metabolites
 GSH – tripeptide (y-glutamyl-cysteinylglycine)
may be as active (N-procainamide) or more toxic
GLUTATHIONE CONJUGATION
(N-acetylisoniazid) than parent compounds
 The acetyl group used in N-acetylation of
xenobiotics is supplied by acetyl-CoA.
 Transfer of the acetyl group from this cofactor to
the accepting amino substrate is carried out by
soluble N-acetyltransferases present in hepatic
reticuloendothelial cells.

 Aromatic compounds with a primary amino group

such as:
o Aniline
GLUTATHIONE CONJUGATION o p-Aminobenzoic Acid
 GSH Conjugation o p-Aminosalicylic Acid
o catalyzed by a family of cytoplasmic o Procainamide(Pronestyl)
enzymes known as glutathione S- o Dapsone (Avlosulfon)
transferases (liver and kidney)  Especially susceptible to N-acetylation.
 Many industrial chemicals, such as benzyl chloride ,
allyl chloride (CH2 = CHCH2CI). and methyl iodide
are known to be toxic and carcinogenic
 The reactivity of these three halides toward GSH
conjugation in mammalian systems is demonstrated
by the formation of the corresponding mercapturic
acid derivatives.
 ACETYLATION POLYMORPHISM
- Catalizes by enzyme N-acetyltransferase  The proportion of rapid and slow acetylators varies
widely among different ethnic groups throughout
the world.
 Eskimos and Asians
o Rapid acetylators
o More likely to show an inadequate
therapeutic response to standard drug
doses
 Egyptians and some Western European groups
o Mainly slow acetylators
o More likely to develop adverse reactions

ACETYLATION

ISONIAZID
 Plasma half-life
o (rapid acetylators) = ranges from 45 to 80
minutes
o (slow acetylators) is about 140 t0 200
minutes
 Slow acetylators
o Greater Adverse effects: e.g.. peripheral
 Acetylation of Sulfanilamide can cause cyrstalluria neuritis and drug-induced systemic lupus
 Metabolites are less water soluble (can cause erythematosus syndrome)
crystalluria, older)  Rapid acetylators
o more likely to develop isoniazid-associated
hepatitis
(acetylhydrazine)

 Slow acetylators
 Increase tendency to cause lupus erythematosus
syndrome to patients taking :
 o HYDRALAZINE AND PROCAINAMIDE contain an aromatic 1,2-dihydroxy group

METHYLATION
 Play an important role in the biosynthesis of many
endogenous compounds
o Epinephrine and melatonin
 And in the inactivation of numerous physiologically
active biogenic amines
o Norepinephrine, dopamine, serotonin, and
histamine
 Coenzyme involved: S-adenosylmethionine (SAM)
 Catalyzed by various cytoplasmic and microsomal
 METHYLTRASFERASES
o Catechol-o-methyltransferase (comt) N- METHYLATION
o Phenol-o-methyltransferase  Antiviral & Antiparkinsonism = Amantadine
(Symmetrel)
o Nonspecific n-methyltransferases
o And S-methyltransferases.  Norephedrine

S- METHYLATION
 Thiol-containing drugs such as:

o propylthiouracil
O-METHYLATION
o 3-dimercapto- I -propanol (BAL)
 Examples of drugs that undergo significant
o 6-mercaptopurine
O-methylation by COMT in humans include:
o (S)(—)a-methyldopa (Aldomet)
o (S)(—)-dopa (levodopa)
o Isoproterenol (Isuprel)
o Dobutamine (Dobutrex)

 COMT selectively O-methylates only the phenolic OH

at C-3.

 Substrates undergoing 0-methylation by COMT must

FACTORS AFFECTING METABOLISM
 Age differences − Acute alcoholism
 Deficiency in enzymes like glucuronyltransferase
o Leading to gray-baby syndrome
o Neonatal hyperbilirubinemia
 Species and strain differences  Vitamins, minerals, starvation, and malnutrition
o Metabolism of Amphetamine occurs by two  Cancer, cirrhosis
main pathways: oxidative deamination or  PATHOLOGIC STATE
aromatic hydroxylation. o Liver diseases
 Human, rabbit,and guinea pig = o Pregnancy
oxidative deamination appears to o Hormonal disturbances (e.g., thyroxine,
be the predominant steroids), and circadian rhythm
 Rat = aromatic hydroxylation
o Cats lack glucuronyltransferase enzymes STEREOCHEMICAL ASPECTS OF DRUG
therefore through sulfoconjugation METABOLISM
o Pigs lack sulfoconjugation
o P-hydroxylation POTENCY
o Pigs-no sulfotransferase  S)(—) enantiomer of warfarin
o Instead of glycine, ornithine is used in  is 5 times more potent as an oral anticoagulant than
conjugation of phenols the (R)( +) warfarin
 Hereditary or genetic factors genetic polymorphism  DIFFERENT PHARMACOLOGICAL ACTIVITIES
 Sex differences o (+ )-a-propoxyphene (Darvon) = analgesic
o Adult male rats metabolize faster o (—)-a-propoxyphene (Novrad) = antitussive
 Enzyme induction (phenobarbital induces o P-hydroxylation is referred
glucuronyltransferases, cabbage, cauliflower and o In humans, Pentazocine forms trans
charcoal broiled foods metabolite
 Exposure to insecticides and pesticides
 Enzyme inhibition (chloramphenicol, isoniazid, REGIOSELECTIVITY
disulfiram and GRAPEFRUIT)  Denotes the selective metabolism of two or more
similar functional groups (e.g.. OCH3, OH,NO2) or
ENZYME INDUCER ENZYME INHIBITOR two or more similar atoms that are positioned in
− Phenobarbital − Metronidazole different regions of a molecule.

− Phenytoin − Erythromycin  Papaverine O-demethylation at the 4th position

 Trimethoprim n-oxide formation at the 3rd position
− Primidone − Disulfiram  Dobutamine o-methylation at the 3rd position
− Rifampicin − Diltiazem

− Carbamazepine − Verapamil

− Chronic alcoholism − Isoniazid

− Smoking − Chloramphenicol

− Griseofulvin − Cimetidine

− Ciprofloxacin

− Clarithromycin

− Ketoconazole

− Grapefruit juice