Organic Pharmaceutical

Chemistry I
By
Dr. Mazin Albasrawy
Lec. 1
 General pathways of drug metabolism
Metabolism (from Greek: metabolē, "change") is a term that is used to describe all
chemical reactions involved in maintaining the living state of the cells and the organism.
The three main purposes of metabolism are:
1. the conversion of food to energy to run cellular processes;
2. the conversion of food/fuel to building blocks for proteins, lipids, nucleic acids, and
some carbohydrates;
3. and the elimination of nitrogenous wastes.
(The word metabolism can also refer to the sum of all chemical reactions that occur in
living organisms, including digestion and the transport of substances into and between
different cells, in which case the above described set of reactions within the cells is called
intermediary metabolism or intermediate metabolism).
 General pathways of drug metabolism
Metabolic reactions may be categorized as
1. catabolic – the breaking down of compounds (for example, the
breaking down of glucose to pyruvate by cellular respiration);
or
2. anabolic – the building up (synthesis) of compounds (such as
proteins, carbohydrates, lipids, and nucleic acids).
Usually, catabolism releases energy, and anabolism consumes
energy.
 General pathways of drug metabolism
When drugs enter the body, they are subject to attack from a range
of metabolic enzymes. The role of these enzymes is to degrade or
modify the foreign structure, such that it can be more easily
excreted. As a result, most drugs undergo some form of metabolic
reaction, resulting in structures known as metabolites.
Very often, these metabolites lose the activity of the original drug,
but, in some cases, they may retain a certain level of activity.
In exceptional cases, the metabolite may even be more active than the parent
drug. Some metabolites can possess a different activity from the parent
drugs, resulting in side effects or toxicity. A knowledge of drug metabolism
and its possible consequences can aid the medicinal chemist in designing
new drugs which do not form unacceptable metabolites. Equally, it is
possible to take advantage of drug metabolism to activate drugs in the body.
This is known as a pro drug strategy.
It is now a requirement to identify all the metabolites of a new drug before
it can be approved. The structure and stereochemistry of each metabolite
has to be determined and the metabolite must be tested for biological
activity.
 Phase I and phase II metabolism
The body treats drugs as foreign substances and has methods of getting rid
of such chemical invaders. If the drug is polar, it will be quickly excreted by
the kidneys. However, non-polar drugs are not easily excreted and the
purpose of drug metabolism is to convert such compounds into more polar
molecules that can be easily excreted.
Non-specific enzymes (particularly cytochrome P450 enzymes in the liver)
are able to add polar functional groups to a wide variety of drugs. Once the
polar functional group has been added, the overall drug is more polar and
water soluble, and is more likely to be excreted when it passes through the
kidneys.
An alternative set of enzymatic reactions can reveal masked polar functional
groups which might already be present in a drug. For example, there are
enzymes which can demethylate a methyl ether to reveal a more polar
hydroxyl group. Once again, the more polar product (metabolite) is excreted
more efficiently.
These reactions are classed as phase I reactions and generally involve
oxidation, reduction, and hydrolysis.
Most of these reactions occur in the liver, but some (such as the hydrolysis
of esters and amides) can also occur in the gut wall, blood plasma, and other
tissues.
• Some of the structures most prone to oxidation are (N -
methyl groups, aromatic rings, the terminal positions of alkyl
chains, and the least hindered positions of alicyclic rings).
• (Nitro, azo, and carbonyl groups) are prone to reduction by
reductases ,
• while (amides and esters) are prone to hydrolysis by peptidases
and esterases respectively.
• For many drugs, two or more metabolic reactions might occur,
resulting in different metabolites; other drugs may not be
metabolized at all.
Drug metabolism has important implications when it comes to
using chiral drugs, especially if the drug is to be used as a
racemate. The enzymes involved in catalysing metabolic reactions
will often distinguish between the two enantiomers of a chiral
drug, such that one enantiomer undergoes different metabolic
reactions from the other. As a result, both enantiomers of a chiral
drug have to be tested separately to see what metabolites are
formed. In practice, it is usually preferable to use a single
enantiomer in medicine or design the drug such that it is not
asymmetric.
A series of metabolic reactions classed as phase II reactions also
occur, mainly in the liver. Most of these reactions are conjugation
reactions, whereby a polar molecule is attached to a suitable polar
‘handle’ that is already present on the drug or has been introduced
by a phase I reaction. The resulting conjugate has greatly increased
polarity, thus increasing its excretion rate in urine or bile even
further.
Phase I
Transformations catalysed by cytochrome P450 enzymes
The enzymes that constitute the cytochrome P450 family are the most
important metabolic enzymes and are located in liver cells. They are
haemoproteins (containing haem and iron) and they catalyse a reaction that
splits molecular oxygen, such that one of the oxygen atoms is introduced
into the drug and the other ends up in water.

NADPH= nicotinamide adenine dinucleotide phosphate oxidase

• There are at least 33 different cytochrome P450 (CYP)
enzymes, grouped into four main families: CYP1–CYP4.
Within each family there are various subfamilies designated by a
letter, and each enzyme within that subfamily is designated by a
number. For example, CYP3A4 is enzyme 4 in the subfamily A
of the main family 3.
• Most drugs in current use are metabolized by five primary CYP
enzymes (CYP3A1, CYP2D6, CYP2C9, CYP1A2, and
CYP2E1).
 Oxidation reactions
1. Oxidation of aromatic moieties (arenes):
 aromatic hydrocarbons hydroxylation is one of the oxidation reactions
of aromatic hydrocarbons. It refers to the mixed function oxidation of
aromatic compounds arenes to their corresponding phenolic
compounds arenols.
 Almost all aromatic hydroxylation reactions are believed to proceed
initially through an epoxide intermediate called arene oxide then
rearrangement of arene epoxide rapidly and spontaneously to the arenol
product in most instances. So most of xenobiotics including drugs
containing aromatic moieties are susceptible to aromatic ring oxidation.
 In humans aromatic hydroxylation is a major route of metabolism for
many drugs containing phenyl rings mostly on para position such as:
i. propranolol.
ii. Phenobarbital.
iii. Phenytoin.
iv. Phenylbutazone.
v. Atorvastatin.
vi. 17α-ethinylestradiol.
vii. S(-)-Warfarine.
viii. Amphetamine
Notes:
• The p-hydroxylated metabolite of phenylbutazone ; oxyphenbutazone is
pharmacologically active and marketed itself as an anti-inflammatory
drug.
• Some enantiomers of drugs have different metabolic pathways where the
pharmacologically more active enantiomer of the oral anticoagulant
warfarine S(-) warfarin undergoes aromatic hydroxylation to form 7-
hydroxywarfarin while the less active enantiomer R(+) warfarin
undergoes keto-reduction metabolism.
 Microsomal aromatic hydroxylation reactions
1. Hydroxylation reaction requirements:
a. It occurs at para position of the arene ring.
b. The substituting group attached to the aromatic ring may influence the
easiness of the hyoxylation reaction where:
i. It proceeds readily in the activated (electron rich rings substituted with
electron donating group OH, NH2, OCH3, CH3).
ii. whereas the electron withdrawing groups that deactivate the ring are
generally slows down or make the aromatic ring resistant to hydroxylation
reaction (Cl-, -N+R3, COOH, SO2NHR).
Example:
The electron donating groups (ring activators) metabolic reaction directing
effect:
The deactivating electron withdrawing groups (2Cl groups, -
NH=C) of the antihypertensive drug clonidine may explain why
this drug undergoes little aromatic hydroxylation in human.
The uricosuric agent probencid with its two electron withdrawing
groups sulfonamide and carboxyl group not undergo aromatic
hydroxylation reaction.
iii. If the drug contains more than one aromatic ring so the more
activated one is more subjected one to oxidation as in case of
aromatic hydroxylation of diazepam occur particularly in the
more activated ring to give 4'-hydroxydiazepam.
Similar thing is encountered in the antipsychotic drug
chlorpromazine and chlorobiphenyl.
c. Most of the phenolic metabolites formed from aromatic
compounds oxidation enters phase II reactions for further
conversion into more polar + water soluble glucuronide or
sulfate conjugates which are readily excreted in urine.
Example:
The major urinary metabolite of the anticonvulsant drug
phenytoin is the o-glucuronide conjugate of p-hydroxyphenytion.