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Why Do Drug’s GetMetabolized?
• Metabolism is the process of preparing foreign chemicals for removal from the body
• Drug action is usually terminated by metabolicprocesses
• The rate of metabolism is one factor indetermining the duration of action of drugs
• Metabolism often occurs in two steps
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Phase I vs. Phase II
• Phase I metabolism involves chemical
transformations, usually catalyzed by
enzymes, including oxidations, reductions,
hydrolyses, and other reactions that prepare
the drug for elimination from the body.
• Most often the products of phase I
metabolism are more polar than the drug
molecule.
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-C-
=Oreduction
-C---OH
-C---OH
-C-OH
=
Ooxidation
-NR, OR, and SR NH2, OH, and SHoxidative dealkylation
-N=N-azo reduction
alcohol acid
-NO2
-NH2
-NH2
nitro reduction
-C-OR
=O
O
-C-OH
=
Hydrolysis of ester
-C-NHR
=O
O
-C-OH
=
+ -NHR
Hydrolysis of amide
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O
CH3
OH
C5H11H3C
H3C
1
2
34
5
6
O
CH2OH
OH
C5H11H3C
H3C
1
2
34
5
6
O
COOH
OH
C5H11H3C
H3C
1
2
34
5
6
O
COOR
OH
C5H11H3C
H3C
1
2
34
5
6
R= Glucornyl group
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Sites of Drug Biotransformation:
Hepatic microsomal enzymes(oxidation, conjugation)
Extrahepatic microsomal enzymes(oxidation, conjugation)
Hepatic non-microsomal enzymes(acetylation, sulfation,GSH,
alcohol/aldehyde dehydrogenase,
hydrolysis, ox/red)
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Cellular localisation of metabolic enzymes
• Endoplasmitic reticulum (ER) of intestinal- and liver cells contain P450
• Cytosol contains Phase II metabolic enzymes
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• Many Phase I oxidations are mediated by cytochrome P450 enzymes.
• Membrane bound proteins - found on the endoplasmic reticulum.
• Heme-containing proteins – porphyrin ring co-ordinating iron at the active site.
• Many iso-forms with different substrate specificities:
• Major human CYP’s: 1A2, 2C9, 2C19, 2D6, 3A4
oxidations
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Structure of P450Substrate access Heme = catalytic centre
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CYP3A4
Family
Subfamily
Individual
protein
Subfamily
Individual
protein
• Cytochrome P450 system:
• Cytochromes are hemoproteins (heme-thiolate) that function to pass electrons by reversibly changing the oxidation state of the Fe in heme between the 2+ and 3+ state and serves as an electron acceptor–donor .
• P450 is not a singular hemoprotein but rather a family of related hemoproteins. Over 1000 have been identified in nature with ~50 functionally active in humans with broad substrate specificity
• - CYPs are in smooth endoplasmic reticulum in close association with NADPH-CYP reductase in 10/1 ratio
• The reductase serves as the electron source for the oxidative reaction cycle
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Cytochrome P450 Isoforms (CYPs) - An Overview
• NADPH + H+ + O2 + Drug NADP+ + H2O + Oxidized Drug
• Carbon monoxide binds to the reduced Fe(II) heme and absorbs at 450 nm (origin of enzyme family name)
• CYP monooxygenase enzyme family is major catalyst of drug and endogenous compound oxidations in liver, kidney, G.I. tract, skin, lungs
• Oxidative reactions require the CYP heme protein, the reductase, NADPH, phosphatidylcholine and molecular oxygen
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• CYP plus arabic numeral (>40% homology of amino acid sequence, eg. CYP1)
• Subfamily - 40-55% homology of amino acid sequence; eg. CYP1A
• Subfamily - additional arabic numeral when more than 1 subfamily has been identified; eg. CYP1A2
• Italics indicate gene (CYP1A2); regular font for enzyme
• Comprehensive guide to human Cyps
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• Common oxidative metabolisms include:
- Aromatic hydroxyations
- Aliphatic hydroxylations - Epoxidation of alkenes
- Dealkylation on heteroatoms
- Oxidation of sulfide to sulfoxides to sulfones
- Oxidation of imines to imine oxides
- Oxidation of alcohols to aldehydes
- Oxidation of aldehydes to carboxylic acids
Oxidative Processes
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Aromatic hydroxylation:-
Hydroxylation usually occurs at the Para-position.
Most phenolic metabolites undrgo further conversion
to polar and water soluble glucuoronide or sulfate
conjugate which are readily excreted.
R RR
OO H
A r e n e A r e n e O x i d e A r e n o l
E p o x i d e
H y d r o l y a s eC Y P 4 5 0
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NH
NH
O O
NH
NH
O O
NH
NH
O O
OH
P-HydroxyPhenytoinPhenytoin
O-Glucuronide Conjugate
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N
HN
Cl
O
4
Cl
Diazepam
p-Chlorobiphenyl
N
S
CH2CH2CH2N(CH3)3
Cl
Chloropromazine
Hydroxylation occurs most readily on rings that are electron-rich, i.e.
those that have electron-donating groups directly attached to the ring
(OH, OCH3, NH2, alkyl groups)
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Dihydrodiol metabolites have been reported in the
metabolism of several aromatic hydrocarbons.
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Enzymatic conjugation with glutathione plays an
important role not only in detoxification of arene
oxides but also in detoxification of a variety of other
chemically reactive and potentially toxic
intermediates.
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Metabolic Oxidation of Alkenes
The oxidative metabolism of olefins (alkenes) is identical to
that of aromatics except that the epoxides that are formed have
little tendency to undergo rearrangement.
The initially-formed epoxides are usually not observed as
metabolites, unless structural features of the molecule make
them stable.
Most typically, they are attacked by epoxide hydrolase to give
trans-dihydrodiols.
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Oxidation of Olefins:-
Epoxides are minor products owing to further
conversion to 1,2-diol
N
NH2O
N
NH2O
N
NH2O
O HOOH
N
NH2O
HOSG
CarbamazepineCarbamazepine-10,11-epoxide
Trans-10,11 Dihydroxycarbamazepine
CYP450 epoxide hydrolyase
Glutathione transferase
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Oxidation of Olefins:-
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Metabolic Oxidation of AlkylGroups
• Aliphatic carbons are also subject to metabolicoxidation. These oxidations can becategorized as:
- Oxidation of aliphatic carbons that are adjacent to
(at an α-position) a functional group - Oxidation of
aliphatic carbons at or near the end of a chain of
aliphatic carbons.
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• The product of these oxidation reactions isan alcohol.
• The carbon undergoing metabolism musthave at least one attached hydrogen.
• The carbon adjacent to a functional group is
the α-carbon. The carbons shown in bold-
face type below are all α-carbons:
CH2R
CH2R R CH2R
O
RXCH2
Metabolic Oxidation of Alkyl Groups
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Oxidation of benzylic carbon atoms
Metabolic Oxidation of AlkylGroups
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Oxidation at carbon atom ά- to carbonyls and lmines:
Metabolic Oxidation of AlkylGroups
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Oxidation at Aliphatic and alicyclic carbon atoms:-Aliphatic carbon centers are subjected to mixed function oxidation:(ω) Oxidation: - oxidation at the terminal methyl group. (ω-1) Oxidation at carbon atom next to the last carbon.
Metabolic Oxidation of AlkylGroups
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Metabolic Oxidation of Alkyl Groups
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The cyclohexyl group is commonly found in many medicinal
agents and in also susceptible to mixed function oxidation
(alicyclic hydroxylation).
Metabolic Oxidation of Alkyl Groups
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Oxidation involving carbon heteroatom systems:-
*Hydroxylation of the α-carbon atom attached
directly to the heteroatom (N, O, S), give unstable
intermediate which decompose with the cleavage
of the carbon- heteroatom bond.
Metabolic Dealkylation
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Hydroxylation or oxidation of the heteroatom (N,S)
only.
N- Hydroxylation
N- Oxide formation
Sulfoxide formation
Sulfone formation
Metabolic Dealkylation
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The C─N system is found in many drugs as
amines or amides as in many naturally as well as
in many drugs as
*Phenothiazines
*Antihistamines
*Tricyclic antidepressants
*β- Adrenergics
*Sympathomimtic phenyl ethylamine
*Barbiturates
*Benzodiazepines.
Metabolic Dealkylation
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The nitrogen could be found as:
1) - aliphatic (tertiary, secoday, primary) and
alicyclic (tertiary,secondary) amines.
2) - aromatic and heterocyclic nitrogen compounds
3) - amides.
N-oxidation.
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The hepatic enzymes that are involved in N-
metabolism are
1) - Hepatic cytp-450 mixed function oxidases
which carry out the α-carbon hydroxylation
reactions and
2) - Hepatic mixed function oxidase called amine
oxidase or N-oxidase. These are NADPH
dependent flavo proteins and do not contain cytp-
450. It requires molecular oxygen and NADPH to
carry out the N-oxidation.
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Tertiary aliphatic and alicyclic amines:
Oxidative removal of alkyl group (particularly methyl group) from tertiary aliphatic and alicyclic amines is carried out by hepatic cytochrome p-450 mixed function oxidase enzymes this reaction is called oxidative N-dealkylation which involve first α-carbon hydroxylation to give a carbinolamine (which is unstable intermediate) this will undergo heterolytic cleavage of C─N bond to give a secondary amine and carbonyl moiety (aldehyde or ketone).
Metabolic Dealkylation
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N-Oxide formation is complicated because of the susceptibility to undergo in vivo reduction back to the tertiary amine. Tertiary amines such as impramine, morphine, and chlorpromazine reportedly form N-oxide products. In some instances, N-oxides possess pharmacological activity. A comparison of impramine N-oxide with impramine indicates that the N-oxide itself possesses antidepressant and cardiovascular activity similar to that of the parent drug.
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Secondary amine either parent compound or metabolites are susceptible to oxidative N-dealkylation, oxidative deamination and N-oxidation but to a much lesser extent.
Oxidation of secondary and primary amines:-
Metabolic Dealkylation
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Metabolic Dealkylation
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N-oxidation of secondary aliphatic and alicyclic amines
N-oxidation of secondary aliphatic and alicyclic amines leads to several N-oxygenated products. N-hydroxylation of secondary amines generates the corresponding N-hydroxylamine metabolites. Often, these hydroxylamine products are susceptible to further oxidation (either spontaneous or enzymatic) to the corresponding nitrone derivatives.
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N-oxidation of secondary aliphatic
and alicyclic amines
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Primary amines:-
Dopamine
Norepinephrine metabolised
Tryptamine by mono amine oxidase (MAO) inactive compound
Serotonine
endogenous primary amines are metabolized by
mono amine oxidase present in mitochonderia of the
cell.
Metabolic Dealkylation
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Primary aliphatic amines (whether parent drugs or metabolites are bio-
transformed by oxidative deamination through carbinolamine pathway or
by N-oxidation.
Metabolic Dealkylation
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N-oxidation of Primary aliphatic
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Aromatic Amines and Heterocyclic Nitrogen
Compounds:-
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Tertiary aromatic amines:
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Amides:-
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Metabolic Dealkylation
• Dealklyation of groups attached to oxygenand sulfur can also occur.
• The mechanism is identical to that of N-dealklyation.
• As before, the carbon directly attached tothe O or S MUST have at least onehydrogen.
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Oxidation involving carbon-sulfur systems:-
Carbon-sulfur functional groups are susceptible to metabolic:
S-dealkylation α-carbon
hydroxylation
desulfuration C=S C=O
S-Oxidation S = O
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S-dealkylation
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Desulfuration
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S-Oxidation
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Many oxidative processes (benzylic, allylic,alicyclic or aliphatic hydroxylation) generatealcohol or carbinol metabolite as intermediateproducts.These if not conjugated, they will furtheroxidized to aldehydes if primary alcohol or toketones if secondary alcohols
Oxidation of alcohols and aldehydes:-
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Oxidation of alcohols and aldehydes:-
RCH2OH
NAD+ NADH
Alcohol dehydrogenase RCHO
NAD+NADH
Aldehyde dehydrogenase
Egs:
Aldeyde oxidase
Xanthine oxidase
RCOOH
2˚ alcohol Ketone
Conjugated
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Oxidation of alcohols and aldehydes:-
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Other oxidative biotransformation pathway:
Aromatization or dehydrogenation
O
OH
C
A
CH
CH3CH2
HO
OH
C
A
CH
CH3CH2
Norgesterol 17 -18-homoestradiol
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CH3
CH3
CH3
OH
C5H11
CH3
CH3
CH3
OH
C5H11
CH3
CH3
CH3
OH
C5H11
Aromatization or dehydrogenation
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Oxidative dehalogenation:-Many halogen containing drugs are metabolized by oxidative
dehalogenation egs:-
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Reductive reaction:-Reductive processes play an important role in the metabolism
of many compounds containing C=O, NO2 and –N=N groups.
Reduction of aldehydes and ketones
These reductions are carried out by aldo-keto reductases. They are found in liver andother tissue (kidney). They have broad substrate specificities and require NADPH ascofactor. Oxido-reductase enzymes that carry out both oxidation and reductionreactions also are capable of reducing aldehydes and ketones, alcohol dehydrogenase isa NAD + dependent oxidoreductase which oxidizes ethanol and other aliphatic alcoholsto aldehydes and ketones. This same enzyme system is capable of reducing carbonylderivatives to their corresponding alcohols.
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Reductive reaction
An NADPH-dependent enzyme called nitro- reductase is the actual reducing agent.
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Azo reduction
Miscellaneouse Reduction:-
Reduction of N-oxide.
Reductive reaction
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Reduction of sulfur – containing functional groups:-
Reductive reaction
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Hydrolysis is the process of breakingbonds by the addition of water.
Functional groups that are most oftenmetabolized by hydrolysis include esters(and lactones) and amides (and lactams).
Hydrolytic Reactions
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Hydrolysis of esters and amides;-
Hydrolytic enzymes that catalyze the cleavage of ester and amidelinkages are present in many organs, various tissues and in plasma.The metabolic products formed (carboxylic acids, alcohol, phenolsand amines) generally are polar and more susceptible toconjugation and excretion than the parent compounds (esters oramide drugs).
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H2NO
N
O
H2N
HN
N
O H2N COOH
esterase
amidase
H2N COOH
slow Hydrolysis
Rapid Hydrolysis
Procainamide
Procaine
Amide hydrolysis appear to the mediated by liver microsomal amidases and esterase
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Phase II Metabolism
Conjugation Reactions
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Drug conjugation pathways (phase II)These are the most important xenobiotic biotransformation
reactions.
Only after conjugation reaction have added an ionic
hydrophilic moiety such as glucuronic acid, sulfate, or glycine
to the xenobiotic, water solubility increased enough to make
urinary elimination possible.
Many conjugative enzyme accomplish this objective, and
these may show stereo specificity towards enantiomers when
a racemic drug is administered.
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H2N
COOH
OH
N-acetylation or
N-glucuronidation
O-glucuronidation or
O-sulfation
acyl glucuronidation or
amino acid conjugation
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O
HOOC
HOHO
OH
OH
Glucuronic acid
Glucuronide Conjugates
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♦Among the most common phase II metabolites
Glucuronide Conjugates
Body has large supply of glucuronic acid,
which is made from D-glucose.
♦ Functional groups susceptible to
glucuronidation include: alcohols and phenols,
carboxylic acids, amines, thiols
♦
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The glucuronide group needs to be activated before itscondensation with the substrate. The reaction betweenUDPGA and the compound is catalyzed by UDP-glucuronyl transferes, it’s a multigene family of isozymeslocated along the endoplasmic reticulum of the liver,epithelial cell of the intestine and other extra hepatictissues. Its unique location in the endoplasmic reticulumalong with CYP450 has important physiological effect incontrolling levels of reactive metabolites present in thesetissues.
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O
HOOC
HOHO
HO
-D-glucose-1-phosphate
UTP PP
Uridine-5-diphospho- -D-glucose(UDPG)phosphorylase
UDPG dehydrogenase
2NAD+
2NADH + 2H
OUDP
UDP-glucuronate
UDP-glucuronyl-transferase
R XH
O
HOOC
HOHO
OH
XR
glucuronide conjugate
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UDP-glucuronate
NHCOCH3
OH
UGTO
HOOC
HOHO
OH
O NHCOCH3
Acetaminophen
UDP-glucuronate
COOHCO
O
COOH
OHOH
HO
O
Ibuprofen
UGT
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H2N
COOH
OH
O
HOOC
HOHO
OH
O-HN
COOH
OH
UGT
Amino salicylic acid
UDP-glucuronate
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SULFATE CONJUGATION
The consequence of this conjugation is its increased aqueous solubility and excretion because the pKa of the sulfate group is about 1-2. The sulfates conjugate are almost totally ionized in physiologic solutions. The cytosolic sulfotransferases are generally asocciated with the conjugation of phenolic steroids, bile acids, neurotransmitters and phenolic drugs.
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NHCCH3
OCH2CH3
=O
NCH2CH3
OCH2CH3
=OOSO3
-
NCH2CH3
OCH2CH3
OH
Phenacetin N-HydroxyphenacetinO-Sulfate conjugate of
N-Hydroxyphenacetin
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CONJUGATION WITH AMINO ACIDS:
Conjugation with amino acids is an important metabolic route in the metabolism of the carboxylic acids prior to elimination. Glycine, the most common amino acid, forms water soluble ionic conjugates with aromatic, arylaliphatic and hetero cyclic carboxylic acids. These amino acid conjugates are usually less toxic than their precursor acids and are excreted readily into the urine and bile
RCOOH + ATP + CoAacyl synthetase
R-CO-S-CoA + AMP
R-CO-S-CoA + R`- NH2
transacylaseR-CO-NH-R` + CoASH
COOH
+ NH2CH2COOHacyl synthetase
CONHCH2COOH
Benzoic acid GlycineHippuric acid
acyl synthetase
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GLUTATHIONE OR MERCAPTURIC ACID CONJUGATESUTATHIO:-
Mercapturic acids are S- derivatives of N- acetylcysteine synthesized from glutathione (GSH). The mercapturic acid pathway appears to have evolved as a protective mechanism against xenobiotic – induced hepato toxicity or carcinogencity, serving to detoxify a large number of noxious substances that we inhale or that are produced daily in human body. Glutathione is a tripeptide (γ – glutamyl cysteinyl glycine) found in most tissues.
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GLUTATHIONE OR MERCAPTURIC ACID CONJUGATESUTATHIO:-
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OP
S
OCH3
OH3C
NO2
GSH
OP
S
OCH3
-O
NO2GSCH3 +
OHP
S
OCH3
OH3C
NO2SG+
Methyl parathion
Pathway a
Pathway b
S-Methylglutathione
S-para nitrophenylglutathion
NO2
Cl
Cl NO2
Cl
Cl NO2
SG
Cl
SG
GSH-HCl
2,4-Dinitrobenzen
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ACETYLATION:-
Acetylation is principally a reaction of amino groups
involving the transfer of acetyl CoA to primary aliphatic
and aromatic amines, amino acids, hydrazines or
sulfonamide groups.
The acetyl group utilized in N-acetylation of xenobiotics is
supplied by acetyl CoA. The transfer of this group to the
amino substrate is carried out by soluble N-acetyl
transferase present in the hepatic reticulendothehial
system.
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It is a common biochemical reaction but appears to be ofgreater significance in the metabolism of endogenouscompounds than for drugs and other foreign compounds.Methylation differs from other conjugation processes in that O-methyl metabolites formed may in some cases have as great orgreater pharmacologic activity and lipophilicity than parentmolecule (e.g. Norepinephrine to epinephrine). Methionine isinvolved in the methylation of endogenous and exogenoussubstrates because it transfers its methyl group via activatedintermediate S-adenosyl methionine (SAM) to substrate underthe influence of methyl transferases.
METYLATION:-
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METYLATION:-
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FACTORS AFFECTING DRUG METABOLISM:-
1.Age differences
2-Species and strain differences
3- Sex differences
4- Enzyme induction
5- Enzyme inhibition
6-Stereochemical Aspects of Drug metabolism:-
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Age: the enzyme system at birth especially in pretermbaby are functionally imature and especially foroxidation and for conjugation with glucuronic acid.
hyperbilirubinemia in infant is due to inability of theinfant to glucuronidase bilirubine. The drugs likechloramphenicol is unable to get conjugated can causefatal grey baby syndrome in neonates .
After first weeks of life the drug metabolic capacityincreases rapidly
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In elderly metabolism is reduced because liver mass
and liver blood flow are decreased .Metabolic
inactivation of drugs is slowed
Drugs persist for longer time and in higher
concentration the must be lowered e.g. tricyclic
antidepressants , antidysrhythmic drugs.
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Species and strain differences
Different animal species may bio-transform a particular xenobiotic by similar or different metabolic pathways.
NH
HN
O O
NH
HN
O O
OH
NH
HN
O O
OH
S(-)-p-Hydroxyphenytoin
R(+)-m-Hydroxyphenytoin
( Man)
( Dog)
Phenytoin
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NH2
NH2
O
HO
p-Hydroxyamphetamine
(Rat)
Oxidative Deamination
Aromatic Hydroxylation
Phenylacetone
(Man, Rabbit and
Guinea pig)
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N
C-NH-NH2
O
Eskimos and Asians Rapid acetylators so there will be
inadquate theraputic response
N
C-NH-NH2
O
Egyptions and
mediterranianSlow acetylators might show toxic effect
Strain DifferenceEven with the same species there could be differences in metabolism (strain difference)
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Sex differences:-The rate of metabolism of xenobiotic show some variation between man and woman which may be due to endogenous sex hormone or hydrocortisone or their synthetic equivalence may affect the activity of the metabolic enzymes e.g. N-demethylation of erythromycin was significantly higher in female than males.
N-demethylation of mepridine was depressed during pregnancy and for woman taking oral contraceptives.
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Enzyme induction:-
It is either increase in the amount of newly synthesized enzyme or increase in theactivity of the enzyme both result in increase in the rate of drug metabolism. This willaffect the pharmacokinetics and pharmacodynamic of a drug with clinical implicationfor the therapeutic actions of a drug and increased potential for drug interactions. As aresult of induction, a drug may be either metabolized more rapidly to metabolites thatare more potent, more toxic or metabolites that are less active than the parent drug,for example phenobarbitone induce microsomal enzyme so when given withwarfarine it increases its rate of metabolism so decrease its anticoagulant affect.
The same happens with contraceptive pills enhance metabolism of estrogen.
Polycyclic aromatic hydrocarbons, pesticides, cigarette smoke all are inducers ofmicrosomal cytp-450 enzyme.
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Inducing Agent Drug Affected PotentailOutcome
Cigarette Smoke Theophylline Asthma Attacks
Rifampine Coumadine Thrombosis
Tegretol OCs Pregnancy
St. John`s Woat Protease inhibitor
Increased Viral Load
Clinical Examples: Induction
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It is the decrease in the rate of metabolism of xenobiotics by using cytochrome P450 inhibitors. Cyp450s inhibitors are divided into:-Reversible inhibition.Metabolite intermediate complexation of cyp450.Mechanism-based inhibition of cyp450.
Enzyme inhibition
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Reversible Inhibition
This is the result of reversible interaction
at the heme-iron active center of cyp450,
or the lipophilic site on the apoprotein or
both e.g cimitidine, diltiazem, quindine
and some other drugs.
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Cyp450 complexation inhibition:-Alkyl amine drugs have the ability to undergo cyp450 mediated oxidation to nitroso alkane metabolites. This process is called metabolite intermediate complexation.
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Mechanism-based inhibition:-
Certain drugs are oxidized by cyp450 generating metabolites that
can bind irreversibly to the enzyme e.g. cyclophosphoamide and its
conversion to acroline and phosphoramide mustared. Spironolacton
and its thio-metabolite that alkylates heme, choramphenicol and its
oxidative dechlorination to an acyl moiety that alkylates cytp450
apoprotein.
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Drug interaction:-
phenylbutazone inhibit metabolism of S(-)warfarin
Increase anticoagulant effect
Hemorrhage
chloram phenicol inhibits metabolism of phenytoin result in toxicity.
Grape fruit juice inhibits some of the cytp450 enzyme increasing the
bioavailability of some drugs like felodipine a calcium channel blocker.
Herbal can interact with drugs too like licorice when taken with steroids
can reduce their metabolism and elimination.
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Food have a great effect on intestinal
cyp450s enzyme,
cauliflower, cabbage, spinach may induce
some of cyp450 or inhibit others.
Two days eating cooked Brussels sprouts
decrease the hydroxylation testosterone
(8oz) of grape fruit juice decrease
sulfoxidation of omprazole.
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Stereochemical Aspects of Drug metabolism
In addition to the physicochemical factors thataffect xenobiotic metabolism, stereochemicalfactors play an important role in thebiotransformation of drugs. Most of themetabolizing enzymes show stereoselectivitywhen one stereoisomes enters intobiotransfermation pathway preferentially, butnot exclusively. Metabolic stereochemicalreactions can be categorized as follows:-
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Substrate Stereo selectivityIt is the preference of one stereorisomer for metabolizing enzyme or metabolic process than the other e.g. the preferred decarboxylation of S-α-methyldopa to S-α-methyldopamine, with almost no reaction for R-α-methyldopa
HO
HO
C
CH3
COOH
S(-)- -MethyldopaS(-)- -Methyldopamine
HO
HO
C
CH3
HL-aromatic a.a.
decarboxylase
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It is preferential formation of one stereoisomeric metabolite over theother. The reduction of ketones to stereoisomeric alcohols and the βhydroxylation of S-α-methyl dopamine to 1R:2S-α-methyl norepirephrine.
Product stereoselectivity
C
CH3
O
N
H
C
O
H2N
R
H HOH
CH3
N+
C
O
H2N
R
+
Acetaphenone Reduced Nicotamide Moeity
of NADPH or NADH
S(-)-Methyl
Phenyl Carbinol
Oxidized Nicotiamide
Moeity of NADP+ or NAD+
NH
NH
S
O
O
C
O
CH3NH
NH
S
O
O
C CH3
HHO
AcetohexamideS(-)-Hydroxyhexamide
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Regioselectivity
Selective metabolism of one of the similar
functional groups that are positioned in different
regions of the molecule.
NH
N
O2N
NO2
5
7 NH
N
H2N
NO2
5
7
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HO
HO
HN
OH
H3CO
HO
HN
OH
Dobutamine
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Extra hepatic metabolism:-
Intestinal metabolism:-
The intestinal mucosa is enriched with cypt450 isoforms,
glucuronosyl transferases, sulfo transferases, and glutathione S-
transferases. The highest concentration of cyp450s occurs in the
duodenum with a gradual tapering into the ileum.
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Lung metabolism:-
Lung may play an important role in the metabolic elimination
or activation of injected or inhaled xenobiotics.
Nasal metabolism:-
Many metabolic enzymes are present in the nasal mucosa
like cyp450, dehydrogenase and other conjugation
enzymes. The nasal decongestant essences, anesthetics,
alcohols, nicotine and cocaine have been shown to be
metabolized by in vitro nasal cyp450.
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Outcome of metabolism
*ToxicMost chemical carcinogens of concern are relatively inert and require activation byxenobiotic metabolizing enzyme before they can undergo reaction with DNA orproteins.
*Pharmacologically active metabolites
These are important in patients with decreased renal function. Some of them have been synthesized and marketed as drug especially for such patients.
*Pharmacologically Inactive metabolites
*Pharmacologically Inactive compound converted to Pharmacologically active metabolites (Pro-drug)
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Metabolism may convert a pharmacologically inactive drug into an active substance. This is may be done deliberately to improve patient acceptability of the agent
Advantegous1- Increased absorption2- Relief of pain at the injection site3- Eliminations of unpleasant taste4-Decrease toxicity5- Increased chemical stability6- Prolonged or shortened action7- Decrease metabolic inactivation
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Carrier linked pro-drugs
These are drugs that have been attached through a metabolically
labile linkage to another molecule. The so called promoiety
which is not necessary for activity but may impart some desirable
property to the drug. Such as increased lipid or water solubility or
site-directed delivery.
Pro-drugs can be divided into:-
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O2N
HN
Cl
OH
O
Cl
O
O- Na+
O
O
O2N
HN
Cl
OH
OH O
Cl
HO
O- Na+
O
O
esterase or water
Chloramphenicol Succinate
Sodium succinate
+
The succinate ester is inactive as antibacterial but this ester is prepared in order to increase water solubility for parental administration. The ester undergoes hydrolysis in plasma to give active drug and succinate.
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Bio precursor pro drugs
Such drugs contain no pro-moiety but rather relay uponmetabolism to introduce the necessary functionality to createan active species.
Types of activation areOxidatives which is the most commonReductivePhosphorylation as antiviral agents
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Reduction
Sulindac
Sulindac is a pro-drug converted to a metabolite that appear to inhibit cyclooxy genase system about 8 time as effective as aspirin.
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