Exam 2 Med Chem Clarke

Ch. 5: Salts & Solubility

Common Hydrophilic Groups
 Polar, ionizable (acidic/basic group) or has a dipole (ex. alcohol w/ its -OH)

Common Hydrophobic Groups

 Things that have a lot of C (hydrocarbon load), halogenated (b/c halogens are
heavy) & ester/ether (they have O’s that can be hydrogen bond acceptors but the
bulk around the O makes them hydrophobic)

What’s More Important for a Drug: Lipid or Water Solubility? Both!

 For dissolution in GI tract: needs solubility
o Solubility = reflection of hydrophilicity (interaction w/ H2O)
 For penetration across membrane: needs permeability
o Permeability = reflection of lipophilicity (interaction w/ lipids)
 Bioavailability= solubility + permeability
o Drug w/ good bioavailability has optimal amount of solubility & permeability
 High water solubility drugs are…
o Good for IV & eye drops
o Ideal for drugs meant to work in urinary tract (ex. Furosemide- pictured on
slide)
o Less likely to undergo extensive metabolism (liver doesn’t have to work so
hard)
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o Quickly solubilized in the gut
 High lipid solubility drugs are…
o Good for transdermal delivery & pulmonary absorption
o More extensively distributed to CNS (must be lipid soluble to cross blood
brain barrier)
o Suitable for intramuscular injections
o More highly plasma protein bound (stays in circulation longer instead of
urinating out quickly)
o Slowly solubilized in gut (or not solubilized at all)
Partition
 Drug bioavailability involves passage through aqueous and lipid media
 Expressed as partition coefficient (P)
o Distribution b/t water & fat
[drug ∈organic( lipid) phase]
o P=
[drug∈aqueous phase ]
 High P more lipophilic (hydrophobic)
 Low P more hydrophilic (lipophobic)

Strategies for Optimizing Solubility

 Convert drug to salt form
o Will only work if it has an ionizable group (acid/base)
 Convert drug to pro-drug
o Gets converted to active drug in vivo
o Usually involves an ester group
 Change drug structures- add/alter functional groups
o Requires drug to be evaluated as a new entity
o Will result in altered drug metabolism vs. parent compound

What is a Salt?
 Ionic compound formed b/t an acidic and basic species results in an electrically
neutral compound
 Will maintain its charge in solution
 Most salts are more water soluble than free acids/bases (‘free acid/base’ implies
no counter ion)
 Salts are more water-soluble (than acids & bases) b/c they dissociate to produce
hydrated ions
o Rate of dissociation can be used to control drug delivery
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*top 3 rows= inorganic, bottom 2 = organic

Different Types of Salts

 Inorganic Salts
o More common
o Always increase water solubility
o Dissociate in solution quickly (fast delivery)
o Formed through non-covalent interactions (ionic)
 Organic Salts
o Can involve some covalent bonding and also non-covalent ionic & polar
interactions
o Dissociate more slowly
o Small organic ions can increase water solubility
o Large organic ions used in salts can actually decrease water solubility
 i.e. to treat local GI diseases, prevent systemic absorption or protect
drug from the environment of the stomach
Salts: Applications to Drug Molecules
 Important to distinguish b/t the ionized form of the drug (due to pH conditions) and
the salt form
 Penicillin V (free acid) vs. Penicillin VK (salt)
o The K is the counter ion of the salt
o Need a certain pH to solubilize the free acid, not the salt form though!
 Timolol maleate: water-soluble organic salt
o Maleate is organic counter ion improves H2O solubility of drug
 Erythromycin stearate: water-insoluble organic salt
o Erythromycin not very stable in stomach acid
o Stearate (C18) is water insoluble delays the solubility of erythromycin
 Slows the drug dissolution to protect drug from stomach  starts to
dissociate once it gets past stomach
 *Water soluble salts are usually C3-4 while water insoluble are closer to C20
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Salt Related Drug Interactions
 Great that ex. basic drug + acidic counter ion from a salt BUT ex. basic drug and
acidic drug can also form a salt (water-insoluble precipitates)
 Water-insoluble precipitates: large organic salts formed b/t two oppositely charged
drugs
 Need to be careful not to co-administer these drugs, especially in an IV
o Cefepime (-) in solution b/c carboxylic acid and Gentamicin (+) in solution b/c
of the amines will combine and form a solid  kill patient!
o Can give to patient separately but NOT together

What is a Pro-Drug?
 Drug that has been covalently modified into a form that is inactive or weakly
activeable to be activated by the body
 Bioactivation: undergoes metabolic activation to release the active drug
o Typically done by hydrolysis in the blood stream (plenty of H2O available to
cut bonds) or liver metabolism (less frequent)
 Note the differences b/t salts & pro-drugs
o When a salt dissociates & goes into solution in the stomach that is just going
into solution, not being activated
o Pro-drug is not formed from an ionic interaction it’s a brand-new form of
the drug
o Salt is NOT a prodrug (even though something has to happen to it before it
goes into solution)
 Pro-drugs are usually more lipid soluble than the parent (active) drug
o Ester prodrugs adding an ester modifies the solubility of the drug makes
it a little more lipid soluble but sometimes the presence of extra H bond
acceptor makes it a little more water soluble

o
 Promotes water solubility & protects stomach from the active drug
(carboxylic acid)

o
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 Pro-drug is very lipophilic slow release of drug due to lipophilic
prodrug
Lipinski’s Rule of 5
 Use Lipinski’s rule of 5 to predict poor oral bioavailability (if it meets more than 1
criteria, good chance it has poor oral bioavailability)
o Bioavailability = function of solubility and permeability
 Rules:
o MW >500  Factor of lipophilicity (permeability)
o LogP >5  Factor of lipophilicity (permeability)
o > 5 hydrogen bond donors Factor of solubility
o >10 hydrogen bond acceptorFactor of solubility
 Other reasons a drug may be orally ineffective or have poor oral absorption:
o Unstable in the acidic environment of the stomach (can be degraded by
stomach)
o Extremely large molecule
 Won’t be able to get to site of action b/c it’s too big
o Undergoes extensive first pass metabolism (metabolism by the liver before
systemic circulation)
 Usually determined experimentally

Biopharmaceutical Classification System (BCS)

 Class 1: high permeability & high solubility
o Simple solid oral dose
 Class 2: high permeability & low solubility
o To make an oral dosage form: can use techniques to increase S.A. (particle
size reduction, solid solution & solid dispersion) or solutions using
solvents/surfactants
 Class 3: low permeability & high solubility
 Class 4: low permeability & low solubility
*as you go from 14 the chance increases that the dosage form will be something other
than oral
 Ex. Enalapril Class 1

o Hydrogen bond acceptors: 7

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o Hydrogen bond donors: 2
o Great oral bioavailability!
 Ex. Dronedarone Class 2

o Hydrogen bond acceptors: 7

o Hydrogen bond donors: 1
o MW is >500 and LogP is >5  expect poor oral bioavailability
 High permeability but low solubility
 Ex. Saquinavir  Class 4

o Hydrogen bond acceptors: 11

o Hydrogen bond donors: 5

Ch. 7: Stereochemistry & Drug Action

Stereochemistry
 Space arrangement of the atoms or 3D structure of the molecule
o Often can be mirror images but are NOT superimposable (ex. your hands)
 Stereochemistry plays a major role in the pharmacological properties b/c:
o Drug targets (usually proteins) are often stereospecific
 Meaning, when you have drugs that are isomers, one isomer will bind
more easily than the other
o The isomeric pairs have different chemical properties
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Optical isomers/ Enantiomers  most common type
 *Set of optical isomers are called enantiomers
 Non-superimposable mirror images
 Must contain at least one chiral carbon atom
o Chiral carbon: C atom that has 4 different ligands attached (by 4 single
bonds) and is thereby asymmetric
o *See slide 4 for practice of chiral carbons!!!
 May have identical physical properties (MP, solubility, logP, pKa) but differ in the
way they interact with biological molecules
o Ex. Thalidomide: One enantiomer can be the drug you want (sedative) and
the other can be a teratogen (can cause birth defects)
o 1962 amendment for safety and efficacy treat enantiomers as separate
compounds
 Nomenclature for Enantiomers
o Based on priority of substituents around chiral carbon [configuration] and
direction in which molecule will rotate plane of polarized light [rotation]
o 2 important properties: configuration (arrangement of substituents) and
rotation (how molecule will rearrange; experimentally determined)
 Assignment of configuration does NOT give you any clue about the
rotation
o Indicating Configuration
 Rectus: R or D clockwise (counting from substituent 123)
 Sinister: S or L counterclockwise
 R/S nomenclature is more widely used
 D/L is seen more in biochem. b/c naming is in reference to
glyceraldehyde
 Thermodynamic equilibrium 50:50 mixture= Racemic mixture
o Indicating Rotation
 Dextrorotatory: d or (+)
 Levorotatory: l or (-)
 Of a pair of enantiomers, one will be (+) and one will be (-)
 determined experimentally plane of polarized light will rotate
in one direction or another
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Enantiomers & Pharmacokinetics

 Absorption: crossing through membrane(s)
o If passive diffusion no difference b/t enantiomers
 B/c they have same hydrophobic/hydrophilic characteristics
o If active transport difference b/t enantiomers
 B/c they have different affinities for the transporters
 Distribution
o Same solubility in circulatory system
o Differences in serum binding protein (Albumin is primary plasma protein)
 Each enantiomer will bind differently b/c albumin is 3D and so are the
enantiomers
 *acidic drugs bind more to albumin (which is basic)
 Metabolism
o Differences due to enzyme stereochemistry
 *most enzymes are in liver
 Excretion
o Same b/c it has to do w/ urine solubility which is the same for enantiomers
 BUT modest stereoselectivity reported for a few drugs

Diastereomers
 Stereoisomers that are non-superimposable & non-mirror images
 Have >1 chiral centers
 If a stereoisomer has 2 chiral centers and we invert one of them diastereomer
o If we invert both enantiomer (*see slide 11)
 May have different chemical & physical properties
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Geometric Isomers (cis-/trans- isomers)
 Occurs as a result of restricted rotation about a chemical bond
o Think of it as the way atoms are arranged across a double bond
 NOT mirror images
 Have different properties across the board (physicochemical properties &
pharmacological activity) b/c different distances separate the functional groups of
these isomers
o If these functional groups are pharmacophores the isomers will differ in
biological activity
o They generally do not fit the same receptor equally well

Conformational Isomers
 Conformational isomerism is the non-identical space arrangement of atoms in a
molecule, resulting from rotation about one or more single bonds
o Refers to flexibility around single bonds
 Almost every drug can exist in more than 1 conformation, so the drug might bind to
more than 1 receptor BUT a specific receptor site might only bind to one specific
conformation the drug can have
o Medicinal chemists sometimes want to prevent formations of different
conformers
o “Conformational blockers” add substituents that make it difficult for the
molecule to be flexible, thus preventing certain conformations
 Structural rigidity
o More flexibility might mean more side effects due to interactions w/ multiple
receptors
o More rigid structure should increase drug activity b/c of specificity
 Incorporating rigidity (conformational blocking/structural rigidity)
o Unsaturated groups
 Double bonds no flexibility around the double bond
 These achieve the most rigidity
 Aromatic ring systems increases hydrocarbon load
o Saturated ring systems
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Stereochemistry & Target Binding

 Stereospecific only one enantiomer binds to the enzyme
 Stereoselective both will bind but one enantiomer is a better fit for the target
 Eutomer Enantiomer w/ high binding affinity for the target
 Distomer Enantiomer w/ low binding affinity for the target

The Chiral Switch

 If the racemic mixture has been shown to be effective (ex. one enantiomer works
and the other doesn’t really but it isn’t toxic) it can be patented and later when
that patent runs out the company can do a “chiral switch” and patent a drug that
contains only the active enantiomeric
 New drug is not considered to be a NCE (new chemical entity)
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Ch. 6: Drug Binding Interactions
Drug Binding
 Refers to how a drug interacts with its biological target
o “drug-target binding”
 Can be covalent or non-covalent in nature

Covalent Bonding (sharing e-)

 Less common drug binding interaction
 Strongest possible bond b/t drug & target attached ‘forever’
 Not sought out as a mechanism for drug-target binding
o Highly therapeutically effective
o Long duration (essentially attached to the enzyme until the enzyme dies)
o Not easily reversible (potential for toxicity)
o Consequences for low specificity (if drug isn’t only going to bind where you
want it topotentially more side effects)
 Examples (drug targets)
o Aspirin (COX1)
o Clopidogrel (ADP binding site on platelets)
o Zidovudine (HIV-1 reverse transcriptase)
 Types of covalent bonds:
o Alkylation
 Highly electrophilic atom/functional group (leaving group) on drug
molecule reacts with nucleophilic atom/functional group on target
 Don’t add alkyl groups but are a rxn that involves an alkyl group
 Ex. Chemotherapy drugs known as alkylating agents
 Specificity is a problemcan kill healthy cells, not just cancer
cells
o Acylation
 Nucleophilic atom/functional group on target attacks ester, lactone
(cyclic ester), amide, lactam (cyclic amide), of carbamate on drug
molecule
 *Nucleophile is (-) so it wants to go after (+) things
 Ex. Beta-lactam antibiotics: serine residue on transpeptidase (target)
attacks beta-lactam ring forms covalent bondinactivates
transpeptidase enzyme (target)
Noncovalent Bonding
 More common in drug-target binding than covalent bonds
 Governed by polarity & ionization
 Weak interactions, but strength in #’s
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o Depends on: distance, steric factors & pH of environment
 Reversible interaction (b/c no e- sharing)
 Represented by affinity [bound drug]:[unbound drug]
 Ionic drug-target interactions
o Occurs b/t acidic and basic groups
 If you have a (+) a.a. in your target you’d use a (-) drug
o Might be pKa dependent determines whether the drug is ionized
(charged) or not
 Dipole drug-target interactions
o Most common type of noncovalent bonding for drugs-targets
o Occur between functional group in which there is a partial charge separation
due to the varying electronegativities of the atoms comprising the functional
groups
o Includes ion-dipole and dipole-dipole interactions
o Target a.a. needs a polar R group (the part of a.a.’s that interacts w/ drugs in
the target)
o Drug needs a polar or ionic moiety
 Hydrogen bondingstrongest type of diploe interaction
o *Recall: when you have a heteroatom bonded to an H, you’ll have a dipole
o Occurs whenever an H atom serves as a bridge between two electronegative
atoms
o H must be covalently bound to one atom and non-covalently bound to the
other
o It’s key for water solubility of drugs
o Can enhance the strength of ionic bonds
 Hydrophobic Interactions
o Not directly related to bond formation but rather to the gain in entropy that
occurs when 2 hydrophobic groups are attracted to one another
o Referred to as van der Walls Interactionsrelated to the proximity of 2
species
o Phenyl stacking: unsubstituted aromatic ring(s) on the drug stack on top of
phenylalanine
 Common type of interaction in drug-receptor
 Stabilization b/t rings
 Chelation & Complexation
o Related to enzyme/target that have a metal component
o Happens when metal ions interact w/ one (complexation) or more
(chelation) electron donating groups/atoms
 Chelation: >1 functional group interacting w/ 1 metal ion
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 Complexation: 1 functional group interacting w/ 1 metal ion
o Make coordinate covalent bonds hybrid b/t covalent and non-covalent
interaction
 Some e- sharing but VERY unequal

Ch. 8: Drug Metabolism

General Principles
 Drug molecules (mostly) are foreign compounds metabolic pathways are used to
enhance the removal of these compounds from the body
o Metabolism often results in reduced toxicity of a compound or activation of a
pro-drug (usually esters or amides)
 Highly water-soluble drugs are easily excreted generally, don’t require extensive
metabolism (b/c easily excreted in urine)
 Highly lipid-soluble drugs tend to require the most extensive metabolism
 Metabolites are generally more water soluble than parent compounds

Factors Affecting Metabolism

 Disease states liver/ kidney disease & immunocompromised patients (organ
transplant, HIV, etc.)
 Age extremes, <5 yrs or >65 yrs
 Gender/sex w/ some drugs you see different metabolites (or ability to metabolize
faster/slower) of certain drugs
o Females can become pregnant affect metabolites
 Environmental smoker, alcohol, drugs, supplements, vitamins, polluted area, etc.
 Genetic Variation pharmacogenomics (how does your individual genome relate
to pharmaceutics in the body)

Types of Metabolic Rxns

 Phase I
o Oxidation, reduction & hydrolysis (esters, amides etc.)
o Can activate or inactivate (create active/inactive metabolites)
o Typically, makes things more water soluble
 Exception is some of the reductive rxns often when you reduce a
functional group that doesn’t increase solubility
o Phase I metabolites often seen in urine (b/c usually more water soluble)
 Phase II
o Conjugations Adding another functional group to the drug (addition of
“moiety” to drug-conjugate)
o No activation! Inactivates and can serve as a detoxification pathway
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o Typically, result in increased water solubility
 Exception ex. addition of a methyl group
CYP450 Oxidation
 Oxidation: gain of O/loss of H
 57 enzymes that all have a heme protein
o Fe center in heme gets reduced
 Associated w/ ~6000 different genes
o Genetic polymorphisms account for genetic differences among patients
 CYP-enzyme family-subfamily (letter)-isoform/isozyme
o Ex. CYP2D6
 Named for max light absorption of 450 nm

Good vs. Poor Metabolizer

Phase I Metabolism
 Oxidation (Mostly CYP450!)
o *Usually addition of -OH group
o Main enzymes: Mixed function oxidases (not highly specific, can react w/
variety of substrates CYP450s) & monooxygenases
 Enzymes mainly found in smooth ER of liver
o Genetic polymorphisms effect oxidative enzymes the most!
 Reduction (gain H/loss of O)
o Enzymes usually very specific to functional groups (aldo-keto reductases,
nitro reductases)
 Mainly found in liver (mostly), kidney & other tissues
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 Hydrolysis
o Important pathway for pro-drugsester (faster) & amide (slower) groups
 Rate is related to steric/electronic protection
o Enzymes are non-specific (as long as drug has a hydrolysable group)
 Found in GI, blood & tissues (anywhere water is present)
o No genetic component (no genetic polymorphisms b/c we all have water)

Phase I: Oxidation
 Oxidation: Aromatic Compounds
o Usually, epoxide intermediate para-hydroxylation (addition of -OH to para
on ring)
 Para metabolite is specific to humans, not really in other species
o More likely to undergo para-hydroxylation:
 Unsubstituted rings
 Rings that contain e- donating groups (ex. ortho/meta methyl or ethyl)

o
 Oxidation: Aliphatic Hydrocarbons
o Alkanes (usually by hydroxylation)
 Usually  & -1…sometimes 
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
o Benzylic Carbon = C attached directly to aromatic ring
 Benzylic C has to be unsubstituted!


o Alkenes (double bond)
 Metabolic oxidation w/ reactive epoxide intermediate diol
 Must have available H’s as leaving group


 *oxidation step gets you to epoxide, hydrolysis gets it to diol ?


 Oxidation: Alkyl Halides *halogens= very lipophilicdrug w/ them last a long time
o CYP450 mediated
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o Oxidative dehydrohalogenation (dehalogenation)
 Add -OH make =O & remove H kick off halogen
o Does not apply to aromatic halogens

o
o When you kick off a halogengenerate a metabolite that is a strong acid (ex.
HCl)
 Cancer drugs use this HCl as part of their mechanism to kill cells
 If you didn’t have a H come off to join w/ the halogen you’d get a free
radical (lone halogen w/ - charge)
 Oxidation: Amines
o Many possibilities involving multiple enzymes
 CYP450 (mainly)
 MAO (primary amines only!)
 FMO
o Possible fates of amine:
 Oxidative deamination (oxidation & loss of NH3/NH4+)
 Add -OH make =O & remove H kick off N
 Get an aldehyde where the N was & ammonia (NH3) byproduct
 N-OxidationNO2
 Add -OH to N form N=O & kick H offcan repeat w/ a 2nd O
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 N-dealkylationremove alkyl group

 Gives aldehyde byproduct

 Oxidation: Alcohols
o Enzyme is alcohol dehydrogenase, NOT CYP450 enzymes
o 1 Alcohols
 Rapid oxidationaldehyde
 Possible to further metabolize to carboxylic acid
o 2 Alcohols: slower oxidation to ketones
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 Oxidation: Ethers
o Oxidative de-alkylation catalyzed by mixed-function (P450s) oxidases
o Products: alcohols, aldehydes & ketones
o Can be followed by phase II conjugations (esp. when alcohol is produced)

 Oxidation: Sulfur Containing Groups

o Thioether: add -OH to C next to Smolecule breaksget sulfhydryl &
aldehyde
o S-Oxidation: add -OH to S form S=O

Phase I: Reduction (gain of H/loss of O)

 Important for compounds with reducible groups
 Products usually undergo subsequent phase II reactions because reductions don’t
usually increase H2O solubility
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 Most common target for reduction is ketone
 Reduction of some functional groups leads to metabolic stereoisomers
o End up w/ chiral center that wasn’t there before

Phase I: Hydrolysis (breaking bond by adding H2O across it)

 Applicable to ester & amide groups (rxn is exploited in production of pro-drugs)
 Don’t need to go through liver (unlike most CYP450 rxns) b/c enzymes are in other
places
 EsterRapid
o Non-specific esterases in liver, kidney
o Pseudocholinesterases in plasma
o Always results in byproduct of carboxylic acid & alcohol
 AmideSlow
o Non-specific esterases, amidases, and carboxypeptidases in various tissues
o Always results in byproduct of carboxylic acid & amine (NH2)
 Rate of hydrolysis related to steric hindrance and neighboring electron withdrawing
groups (electronic protection)
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Phase II
 Phase I usually generate (expose) functional groups (-OH, -NH 2, -COOH) that are
suitable for a phase II reaction
 Reactions may occur at any point
o Phase II doesn’t have to happen after phase I but the products are usually
end products
 Metabolites are usually inactive often represents final step (excretion)
 Require certain (reactive) functional groups
o Ex. -OH, -NH2, -COOH & -SH
 Common feature: transferase enzyme & coenzyme
o Transferase transfers conjugate onto the drug
 Purpose: make something a lot more water soluble
o By attaching small molecule that is polar/ ionizable
 Result: renal excretionb/c made soluble enough
 Conjugates that increase water solubility:
o Glucuronic acid = top phase II metabolite
o Sulfate group give molecule a charge
o Amino acid conjugates make molecule ionizable
 Other phase II conjugatesdon’t increase water solubility, just stop activity of drug
o Detoxification: remove something that will have an adverse effect
 Glutathione (GHS) conjugation
o Terminate or attenuate drug pharmacology stop activity of drug
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 Methylation (attachment of methyl group)
 Acetylation (attachment of an acetyl group)
 Functional groups for phase II
o GSH = glutathione (phase II detox)
 Goes after things with high toxicity (halogens, epoxides)
 Only phase II that does not require a heteroatom (S, O, N)

Phase II: Types of Reactions

 Glucuronic Acid Conjugates (Glucuronidation)
o Most common phase II reaction
o Reaction site must be an election rich
nucleophilic heteroatom (X):
 O-glucuronides
 N-glucuronides
 S-glucuronides
o Excretion: once gluc. is addedexcreted differently depending on MW
 MW <250 urine
 350>MW>250 either
 MW > 350  bile

 Sulfate Conjugation/formation
o Alternative route for phenols (most common), alcohols & amines
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nd
 2 choice because if you don’t have enough glucuronic acid this is the
direction it goes
 1st choice in children though, b/c they don’t have enough glucuronide
o More water-soluble conjugate and often a detox method (NOT primary
method) b/c it takes care of reactive things

 Amino Acid Conjugations

o Important for metabolism of carboxylic acid
 Only used w/ carboxylic acid!
o Only glycine & glutamine can be used (for humans)
o Makes drug more soluble

 Glutathione (GSH) Conjugation- makes drug less soluble

o Important functional group on glutathione is -SH (sulfhydryl)
o Step in elimination of compounds with electrophilic center
o Glutathione concentration is high in cytoplasm, especially in liver and kidney

 Methylation- makes drug less soluble (excreted in feces)

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o Minor metabolic pathway (don’t see often)
o Occurs in phenols, carboxylic acid, thiols, and amino groups
o Specific methyltransferases + SAM (s-adenosylmethionine, a coenzyme)

 Acetylation- reactions rarely increase water-solubility

o Major route for aromatic amines (weak bases)
o Requires: AcetylCoA + N-acetyltransferase (NAT)
 NAT has the most pharmacogenomics variability!
 Low levels of NAT  slow acetylator (about half the population)

Phase II
More water soluble Less water soluble
o Glucuronide o Glutathione (GSH)
o Sulfate o Methylation
o Amino Acid (Glycine & Glutamine) o Acetylation