By Dr. fatmah alomary

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Drug Metabolism

• By Dr. fatmah alomary
• Falomary_at_ksu.edu.sa

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Drug Metabolism

• Drug metabolism is the transformation of foreign
  compounds ( xenobiotics) into a water soluble
  derivatives which can be easily eliminated in
  the urine.

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Example
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In General , the metabolism of xenobiotics takes
place in two steps known as phase I phase II
reactions
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Phase I ( functionalization reaction )

• Is the process of increasing of the
  hydrophilicity of lipophilic drug by introducing
  a polar functional group eg OH,COOH,NH2,SH to
  the molecule through oxidative, reductive
  hydrolytic biotransformations.

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Phase II ( conjugation reactions )

• Is Linking of an endogenous solubilizing moiety
  either to the original drug (if polar function is
  already present) or to the phase I metabolite.
• Common solubilizing groups are glucuronic acid,
  various amino acids or sulphate groups.
• The conjugate molecule, being more polar and
  water-soluble, is usually excreted via the renal
  route

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Effect of metabolism on the therapeutic activity
of drugs
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Factors affecting drug metabolism

• Genetic factors
• Physiological factors
• Pharmaceutical factors
• Pharmacodynamic factors.
• Enviromental factors.

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Genetic factors

• Biological half life (t1/2) of various drug

Genetic
Polymorphism Different expression of
metabolizing enzymes according to the Race
(ethnicity)
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Physiological factorsAge ,Gender,maternity
status,liver function Nutritional status. eg
Age which is the ability of the body to
metabolize the drug lower in v. young elderly.
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Pharmacodynamic factors

• The dose, the route and the frequency of
  administration of drugs Drug interaction can
  affect their metabolic profiles.
• Drugs given too frequently may overload the
  metabolic system available to it, leading to
  elevated blood and tissue levels of the drugs.
  The effect of protein binding also influences the
  metabolism.
• Drug interactions for example-
• Phenobarbital stimulate the metabolism of
  Diphenylhydantoin.
• Plasma Concentration of anticoagulants such as
  Warfarin are reduced by simultaneous application
  of barbiturate

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Enviromental Factors

• Inhaled gases,toxins egNicotine (cigarette 8
  to 10 mg )
• -Acute nicotine exposure
• (From insecticide sprays or tobacco)
• Nausea, vomiting, salivation, diarrhea,
  dizziness, mental confusion, weakness
• -Fatal exposure (60 mg fatal for adult)
• Decreased blood pressure, irregular pulse,
  convulsions, respiratory failure and death
• -Cotinine - Major metabolite
• -Lung First site of metabolism
• -Liver Major site
• -Half-life about 2 hours

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(Phase I (Functionalization reactions

• Oxidations (electron removal, dehydrogenation and
  hydroxylation)
• Reduction ( electron donation, hydrogenation
• and removal of oxygen )
• Hydrolytic reactions of amides esters.

-Two general types of enzyme systems take part in
these reactions -a) Microsomal Mixed Function
Oxidases (MFOs) Flavoprotein, NADPH-monooxygenase
Cytochrome P450 -b) Non-cytochrome oxidizing
enzymes. Xanthine oxidase Alcohol/aldehyde
dehydrogenase
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I) Oxidation Reactions

• The main enzymes involved in the oxidation of
  xenobiotics called mixed function oxidases
  (MFO) or monooxygenases, found mainly in the
  liver but also occur to less extent in other
  tissues.
• Cytochrom P450 ( CYP450 ) catalyze the majority
  of Drug metabolism oxidation reactions.
• MFO is an old terminology,the enzyme are most
  frequently known as CYP450 Superfamily

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-The enzyme systems carrying out this
biotransformation are referred to as
monooxygenases or microsomal (non specific
enzymes in liver). -The reaction requires both
molecular oxygen and the reducing agent
(Activation of O2 ? 1 atom goes to organic
molecule, the other reduced to H2O0. -NADPH
(nicotinamide adenosine dinucleotide
phosphate). -Monooxygenases are made up of
several components- 1) Cytochrome P-450 which
is the most important component and is
responsible for transferring an oxygen atom to
the substrate R-H.
2) Cofactors supply the reducing equivalents
(electrons) needed in the overall metabolic
oxidation
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a) NADPH. Dependent cytochrome P-450
reductase. b) NADH. Linked cytochrome
P-450. Cytochrome P-450 is found in high
concentration in the liver, also present in other
tissues like lung, kidney, intestine, skin,
placenta and adrenal cortex. C) FMO is also
a member of the mono-oxygenase system
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It is characterized by the substrate
nonspecificity, this versatility may be
attributed to the multiple forms of the enzyme. -
Consequently, the biotransformation of a parent
xenobiotic to several oxidized metabolites is
carried out not just by one form of P-450 by
several different forms. -It is now actually
proven that the metabolism of drug is carried out
by different isoforms,members of the CYP450
superfamily,egCYP2A1,CYP2D6,CYP3A4etc
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Classification

• -A large number of families (at least 18 in
  mammals) of cytochrome P-450 (abbreviated CYP)
  enzymes exists as well as many subfamilies.
• each member catalyzes the biotransformation of a
  unique group of drugs
• -CYP450 SUPERFAMILY classified according to
  sequence homology.
• -High homology gt 90, intermediate gt 60
  Low gt 40
• -FAMILY members have gt 40 homology (low). E.g.
  CYP1 vs. CYP2
• -SUBFAMILY members have gt 60 homology
  (intermediate). E.g. CYP2A vs. CYP2B
• ISOFORM CYP2A1, CYP2A2. (High)

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Major reactions of oxygenation catalyzed by
CYP450
1-Carbone oxidation reaction
2-N-Oxygenation reactions.
3-S-oxidation .
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2-N-Oxygenation reactions
1-Carbone oxidation reactions
a)Hydroxylation of Saturated aliphatic C atom.
ring b)Hydroxylation of aromatic aliphatic
c)Oxidation of unsaturated
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Major reactions of oxygenation catalyzed by CYP450
3-S-oxidation .
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Oxidation reactions

• Carbon oxidation reaction
• A) Aliphatic hydroxylation
• B) -Aromatic hydroxylation
• N-Dealkylation
• N-oxide formation
• Oxidative Deamination
• O-Dealkylation reactions
• S-Dealkylation .
• S-oxidation reactions

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A) Aliphatic hydroxylationi)saturated aliphatic
carbon atoms

• Saturated aliphatic C-H bonds are metabolised by
  hydroxylation on the penultimate carbon atom (?-1
  )and on the ultimate carbon(?)to lesser extent.

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ii)Enzymatic introduction of a hydroxyl group
into cyclohexane ring generally occurs at C-3 or
C-4

• -In humans the trans-4-hydroxycyclohexyl product
  has been reported as a major metabolite of
  acetohexamide ( hypoglycemic agent )

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• iii(Terodiline
• Aromatic p-hydroxylation predominate with
  R-isomer where as benzylic hydroxylation is
  preferred with S-isomer.

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iv)Tolbutamide
CYP450
Tolbutamide
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CYP450
Pentobarbital
CYP450
CYP450
Ibuprofen
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CYP450
Phenmetrazine
CYP450
Valproic Acid
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(v
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VI)Oxidation at Benzylic Carbon Atoms Benzylic
carbon atoms are susceptible to oxidation forming
the corresponding alcohol or carbinol which is
further oxidized to or conjugated with glucuronic
acid.
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)Oxidation at Carbon Atoms Alpha to Carbonyl and
Imines An important class of drugs undergoing
this type of oxidation is the benzodiazepines
e.g. diazepam and flurazepam. The C-3 carbon atom
is ? to both a lactam carbonyl and an immino
functionality.
Hydroxylation of the carbon atom ? to carbonyl
group generally occurs only to a limited extent
e.g. glutethimide
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vi) Aliphatic hydroxylation (alkene epoxidation).
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B) Aromatic Hydroxylation (Oxidation of aromatic
rings) Aromatic epoxidation It involves
oxidation of aromatic compounds (arenes) to their
phenolic metabolites (arenols).
It is a major route of metabolism for many drug
containing phenyl groups.
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Rules for Aromatic Oxidation -In most of drugs
containing aromatic moieties, microsomal aromatic
hdroxylation occurs at the para-position. -Micros
omal aromatic hydroxylation reactions proceed
most readily in activated (electron-rich) rings
e.g. rings containing electron donating group as
NH2 group. -Deactivated aromatic rings (e.g.,
those containing electron-withdrawing groups as
Cl, NR3, COOH, SO2NHR are generally slow or
resistant to hydroxylation.
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For compounds in which two aromatic rings are
present, hydroxylation occurs preferentially in
the more electron-rich ring.
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When para- position of aromatic ring is occupied
the oxidation occurs in ortho- position.
Estradiol

CYP450
CYP450
CYP450
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Metabolic oxid. of C-N C-S involve
hydroxylation of alpha carbone atom attached
directly to heteroatom(N,O,S)
2) N-dealkylation
General Mechanism a) Hydroxylation of the
?-carbon atom attached directly to the heteroatom.
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b) Hydroxylation or Oxidation of the Heteroatom
(N, S only)
Hydroxylol
This reaction is catalyzed by cytochrome P-450
and N-oxide amine oxiases or N-oxidases.
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?cont..N-dealkylation It involves oxidation
of tertiary and secondary amines. oxidative
alpha-hydroxylation at alpha-C then dealkylation.
i) Oxidation of Tertiary Aliphatic Amines It
is characterized by oxidative removal of alkyl
group (particularly CH3 group) form tertiary
aliphatic and alicylic amines. Removal of the
first alkyl group occurs more rapidly than the
removal of the second alkyl group.
Bisdealkylation may occur but very slowly.
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i)
ii)
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?
-Oxidation of Secondary Amines
iii
Amines can undergo deamination. Amphetamine for
example is deaminated to phenyl acetone and
ammonia

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CYP450
Nicotine
Cotinine
CYP450
CYP450
Norcotinine
Nornicotine
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3) N-Oxide formation

-The biotransformation of amines is the same
as the carbon and nitrogen oxidation reactions
seen for aliphatic amines but tertiary and
secondary aromatic amines are rarely encountered
in medicinal agents
.
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Mephentermine
Mephentermine N-Oxide
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4) Oxidative Deamination
Oxidative deamination of most exogenous primary
amines is carried out by the mixed oxidases.
However, endogenous primary amines, such as
dopamine, norepinephrine, tryptamine and
serotonin, are metabolized through oxidative
deamination by monoamine oxidases (MAO).
Amines can undergo deamination. Amphetamine for
example is .. deaminated to phenyl acetone and
ammonia .
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Mechanism
.
This process is similar to N-dealkylation, in
that it involves an initial ?-carbon
hydroxylation reaction to form a carbinolamine
intermediate, followed by carbon-nitrogen
cleavage to the carbonyl metabolite and ammonia
in primary amines
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5) Oxidative Dealkylation
Oxygen alkyl groups are removed by liver
microsomal preparation by a mechanism involves
a-hydroxylation of the alkyl groups
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i)The metabolism of these systems occurs
through oxidative O-dealkylation by microsomal
enzymes.
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. 6) S-dealkylation
Methitural
S-demethylated metabolite
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i-Oxidation of Sulfur
Thioethers or sulfides, for example,
Chlorpromazine and Cimetidine are oxidized to
their sulphoxides
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ii- Desulfuration
It is the conversion of
thione (C S) to the corresponding (C O).

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II.Reduction
-Play an important role in the metabolism of
compunds containing azo,nitro,carbonyl. -Bioreduct
ion of nitro azo lead to amino derivatives
,where as carbonyl compounds reductions lead to
alcohol analogs
1-Azo-reduction
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2-Nitro reduction
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3-Reduction of Carbonyl group

• E.g. The opioid receptor antagonist Naltrexone
  is reduced in humans to its secondary alcohol
  metabolite

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Bio reduction of sedative hypnotic Chloral
hydrate yields trichloroethanol. This oxidation
is non- microsomal is believed to take place by
alcohol dehydrogenase.
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4-Reduction of Sulphur containing group
prodrug inactive
. active
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III-Hydrolytic ReactionsMetabolism of ester
amide linkage in many drugs catalyzed by
hydrolytic enzyme(esterase and amidasea).
Procaine
Procaineamide
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Example
Procaine Short acting local anesthetic
Procainamide Long acting antiarrhythmic
T1/2 2.5-4.5 hr
T1/2 40-84 second
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Ester vs. Amide bond

• The duration of actions of ester drugs are less
  than the amide analogues.why?
• Procaine (ester type) injection or topical is
  usually shorter acting than its amide analogue
  procainamide administered similarily
• Ester bond is relatively weaker than amide bond,
  it will be rapidly hydrolyzed by esterase enzyme

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Nucleophilic attack of hydroxide anion on ester
and amide
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• Esterases and Amidases
• Esters are more prone to hydrolysis.
• Converted to more W.soluble carboxylic acids.
• E.g. Meperidine, Succinylcholine.
• Sterically hindered esters might be excreted
  unchanged??? Why?

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• Amides
• More resistant to hydrolysis than esters why?,

• Advantage Procaine vs. Procainamide.

Procaine ester, very short half life, destroyed
shortly after entering circulation

• Procainamide

• longer half life than procaine.

more than 60 excreted unchanged