metabolic changes

1. Metabolic Changes of Drugs and Related
Organic Compounds
3rd stage/ 1st semester
Lecture 3
Shokhan J. Hamid

2. •Metabolism plays a central role in
the elimination of drugs and other
foreign compounds from the body.
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3. • If lipophilic drugs, or xenobiotics, were not metabolized to
polar, readily excretable water-soluble products, they would
remain indefinitely in the body, eliciting their biological
effects.
• Thus, the formation of water-soluble metabolites not only
enhances drug elimination, but also leads to compounds that
are generally pharmacologically inactive and relatively
nontoxic.
• drug metabolism reactions have traditionally been regarded
as detoxification processes!!!
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4. General Pathways of Drug Metabolism
• Drug metabolism reactions have been divided into
two categories:
• phase I, functionalization and phase II, conjugation
reactions.
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6. • Phase I, include oxidative, reductive, and hydrolytic
biotransformations.
• The purpose of these reactions is to introduce a polar functional
group(s) e.g., OH, COOH, NH2, SH into the xenobiotic molecule
to produce a more water-soluble compound.
• This can be achieved by direct introduction of the functional
group e.g., aromatic and aliphatic hydroxylation or by modifying
or “un masking” existing functionalities e.g., reduction of ketones
and aldehydes to alcohols; oxidation of alcohols to acids and etc..
• Although phase I reactions may not produce sufficiently
hydrophilic or inactive metabolites, they generally tend to provide
a functional group on the molecule that can undergo subsequent
phase II reactions.
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7. • The purpose of phase II reactions is to attach small, polar,
and ionizable endogenous compounds such as glucuronic
acid, sulfate, glycine, and other amino acids to the functional
groups of phase I metabolites or parent compounds that
already have suitable existing functional groups to form
water-soluble conjugated products.
• Conjugated metabolites are readily excreted in the urine and
are generally devoid of pharmacological activity and toxicity
in humans.
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8. • Other phase II pathways, such as methylation and
acetylation, terminate or attenuate biological activity,
whereas glutathione (GSH) conjugation protects the body
against chemically reactive compounds or metabolites.
• Thus, phase I and phase II reactions complement one
another in detoxifying, and facilitating the elimination of,
drugs and xenobiotics.
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9. • Example:
• The principal psychoactive constituent of marijuana, Δ1-
tetrahydrocannabinol.
• This lipophilic molecule undergoes allylic hydroxylation to give 7-
hydroxy-Δ1-THC in humans which is more polar than its parent
compound.
• The 7-hydroxy metabolite is further oxidized to the corresponding
carboxylic acid derivative. Subsequent conjugation of this metabolite
(either at the COOH or phenolic OH) with glucuronic acid leads to
water soluble products that are readily eliminated in the urine.
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11. • In the series of biotransformations, the parent Δ1-THC
molecule is made increasingly polar, ionizable, and
hydrophilic.
• The attachment of the glucuronyl moiety (with its ionized
carboxylate group and three polar hydroxyl groups to the
Δ1-THC metabolites notably favors partitioning of the
conjugated metabolites into an aqueous medium.
• This is an important point in using urinalysis to identify
illegal drugs.
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12. Sites of Drug Biotransformation
• Although biotransformation reactions may occur in many
tissues, the liver is, by far, the most important organ in drug
metabolism.
• Because it is:
• well-perfused organ.
• particularly rich in almost all of the drug-metabolizing
enzymes.
• Another important site, especially for orally administered
drugs, is the intestinal mucosa, which contains the CYP3A4
isozyme and P-glycoprotein that can capture the drug and
secrete it back into the intestinal tract.
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13. • Orally administered drugs that are absorbed through the GI tract must
pass through the liver before being further distributed into body
compartments.
• Therefore, they are susceptible to hepatic metabolism known as the
first-pass effect before reaching the systemic circulation.
• Depending on the drug, this metabolism can sometimes be quite
significant and results in decreased oral bioavailability.
• For example, in humans, several drugs are metabolized extensively by
the first-pass effect, the following list includes some of those drugs:
• Isoproterenol, Morphine, Propoxyphene, Lidocaine, Nitroglycerin,
Propranolol, Meperidine, Pentazocine and Salicylamide.
• Lidocaine, is removed so effectively by first-pass metabolism that
they are ineffective when given orally and Nitroglycerin is
administered buccally to bypass the liver.
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15. • Because most drugs are administered orally, the intestine appears to
play an important role in the extra hepatic metabolism of xenobiotics.
• Esterases and lipases present in the intestine may be particularly
important in carrying out hydrolysis of many ester prodrugs.
• Bacterial flora present in the intestine appear to play an important role
in the reduction of many aromatic azo and nitro drugs (e.g.,
sulfasalazine).
• Intestinal β-glucuronidase enzymes can hydrolyze glucuronide
conjugates excreted in the bile, thereby liberating the free drug or its
metabolite for possible reabsorption (enterohepatic circulation or
recycling).
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16. Role of Cytochrome P450 Monooxygenases in Oxidative
Biotransformations
• Of the various phase I reactions, oxidative biotransformation
processes are, by far, the most common and important in drug
metabolism.
• The oxidation of many xenobiotics (R-H) to their corresponding
oxidized metabolites (R-OH) is given by the following equation:
• RH + NADPH + O2 + H+ ROH + NADP+ + H2O
• The enzyme systems carrying out this biotransformation are referred
to as mixed-function oxidases or monooxygenases.
• The reaction requires both molecular oxygen and the reducing agent
NADPH (nicotinamide adenosine dinucleotide phosphate).
• During this oxidative process, one atom of molecular oxygen (O2) is
introduced into the substrate R-H to form R-OH and the other oxygen
atom is incorporated into water
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17. • The mixed-function oxidase system is actually made up of several
components, the most important being the superfamily of CYP
enzymes which are responsible for transferring an oxygen atom to
the substrate R-H.
• The CYP enzymes are heme proteins, the heme portion is an iron-
containing porphyrin called protoporphyrin IX, and the protein
portion is called the apoprotein.
• CYP is found in high concentrations in the liver, the major organ
involved in the metabolism of xenobiotics.
• The presence of this enzyme in many other tissues (e.g., lung,
kidney, intestine, skin, placenta, adrenal cortex) shows that these
tissues have drug-oxidizing capability too.
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18. • The name cytochrome P450 is derived from the fact that the reduced (Fe
+2) form of this enzyme binds with carbon monoxide to form a complex that
has a distinguishing spectroscopic absorption maximum at 450 nm.
• One important feature of the hepatic CYP mixed function oxidase system is
its ability to metabolize an almost unlimited number of diverse substrates by
various oxidative transformations.
• The CYP monooxygenases are located in the endoplasmic reticulum, a highly
organized and complex network of intracellular membranes that is
particularly abundant in tissues such as the liver.
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20. A. OXIDATIVE REACTIONS

21. 1. Oxidation of Aromatic Moieties:
• Aromatic hydroxylation refers to the mixed-function oxidation of
aromatic compounds arenes to their corresponding phenolic
metabolites arenols.
• Almost all aromatic hydroxylation reactions are believed to proceed
initially through an epoxide intermediate called an arene oxide,
which rearranges rapidly and spontaneously to the arenol product in
most instances.
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22. • Arene oxide intermediates are formed when a double bond in
aromatic moieties is epoxidized.
• Arene oxides are of significant toxicologic concern because these
intermediates are electrophilic and chemically reactive.
• Arene oxides are mainly detoxified by spontaneous rearrangement
to arenols, but enzymatic hydration to trans-dihydrodiols by
epoxide hydrase enzyme and enzymatic conjugation with GSH by
GSH S-transferase also play very important roles.
• If not effectively detoxified by these three pathways, arene oxides
will bind covalently with nucleophilic groups present on proteins,
DNA, and RNA, thereby leading to serious cellular damage.
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24. • In humans, aromatic hydroxylation is a major route of metabolism
for many drugs containing phenyl groups.
• Important therapeutic agents such as propranolol, phenobarbital,
phenytoin, phenylbutazone ,atorvastatin, 17-ethinylestradiol, and
(S)(-)-warfarin, undergo extensive aromatic oxidation.
• In most of the drugs just mentioned, hydroxylation occurs at the
para position.
• Most phenolic metabolites formed from aromatic oxidation
undergo further conversion to polar and water soluble glucuronide
or sulfate conjugates, which are readily excreted in the urine.
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26. • The para-hydroxylated metabolite of phenylbutazone, is
pharmacologically active and has been marketed itself as an
anti-inflammatory agent.
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27. • The two enantiomeric forms of the oral anticoagulant warfarin
(Coumadin), only the more active S(-) enantiomer has been
shown to undergo substantial aromatic hydroxylation to 7-
hydroxywarfarin in humans.
• In contrast, the (R)(+) enantiomer is metabolized by keto
reduction.
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28. • The substituents attached to the aromatic ring may influence the ease of
hydroxylation.
• Aromatic hydroxylation reactions appear to proceed most readily in
activated (electron-rich) rings, whereas deactivated aromatic rings (e.g.,
those containing electron-withdrawing groups Cl, -NR3, COOH, and etc..
are generally slow or resistant to hydroxylation.
• The deactivating groups present in the antihypertensive clonidine may
explain why this drug undergoes little aromatic hydroxylation in humans.
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29. • The uricosuric agent probenecid, with its electron-
withdrawing carboxy and sulfamido groups, has not been
reported to undergo any aromatic hydroxylation.
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30. • In compounds with two aromatic rings, hydroxylation occurs
preferentially in the more electron-rich ring.
• For example, aromatic hydroxylation of diazepam (Valium) occurs
primarily in the more activated ring to yield 4-hydroxydiazepam.
• A similar situation is seen in the 7-hydroxylation of the
antipsychotic agent chlorpromazine and in the para-hydroxylation
of p-chlorobiphenyl to p-chloro-p-hydroxybiphenyl.
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31. • Recent environmental pollutants, such as polychlorinated
biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD), have attracted considerable public concern over their
toxicity and health hazards.
• These compounds appear to be resistant to aromatic oxidation
because of the numerous electronegative chlorine atoms in their
aromatic rings.
• The metabolic stability coupled to the lipophilicity of these
environmental contaminants probably explains their long
persistence in the body once absorbed
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32. End
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