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Metabolism
•Chemical transformaion of xenobiotics
•Occurs in mostly in liver (enzymatic prosesses)
•Convertion into more hydrophil. subst. - excretion urine
•May convert pro-carciogenics into cytotox., muthagenic compounds
•Different persons may have differences in methabolism (genetic diff., physiol. factors)
•Methabolism of one xenobiotic may influence metab. of amother
Xenobiotics•Drugs•Other foreign non-essential compounds
Metabolism in non-hepatic tissue•Intestine mucosa•Kidney•Lung•Bacteria in GI-tract
First-pass metabolism:Xenobiotic metabolized before reachinggeneral circulation
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Pathways of metabolism
Phase 1: Biotransformation
Attachment of new functional groups, transformation of exist. funct. groups
oxidation, reduction, hydroxylation, hydrolysis etc.
Phase 2: Conjugation.
Masking of an exist. funct. group by for instance
acetylation, glycosylation, attachment amino acid etc
More hydrophilic drug
Renal excretion
O OHHO
NCH3
Morphine
Demethylation
Phase 1 O OHHO
NH
Conjugationglucuronic acid
Phase 2 O OHO
NH
O OHCO2H
OHHO
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Phase 1 react. not involving CYP450
microsome: Artefactual spherical particle, not present in the living cell, derived from pieces of the endoplasmic reticulum present in homogenates of tissues or cells: microsomes sediment from such homogenates when centrifuged at 100 000 g and higher: the microsomal fraction obtained in this way is often used as a source of mono-oxygenase enzymes.
Other microsomal enzymesAzoreductase
Nitroreductase
Flavinmonooxygenase-FMO (N and S-ox.)
Peroxidases
NN NH2
SO
OH2N
H2NNH2S
O
OH2N
Prontocil Sulfanilamide
R NO2 R NH2
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Flavinmonooxygenase-FMOCont. FAD
N
N
N
NHH3C
H3C
O
O
H OHOHOHH
H
OPO3 2-
Flavin mononucleotide
FMN
N
HN
NH
NHH3C
H3C
O
O
H OHOHOHH
H
OPO3 2-
FMNH2
N
N
N
NHH3C
H3C
O
O
H OHOHOHH
H
O P OO
OH
O
OHO O
HO OH
N
N
N
N
NH2
FAD
N
HN
N
NHH3C
H3C
O
ORFADH2
Flavin adenine dinucleotide
N
N
N
NHH3C
H3C
O
O
H OHOHOHH
H
OH
Riboflavin(Vit B2)
N
N N
N
NH2
O
ORHO
OP
O
O
OH
P
OO
OHHO
N
O
HO
O
NH2
N
N N
N
NH2
O
ORHO
OP
O
O
OH
P
OO
OHHO
N
O
HO
O
NH2
NADH
H H
Nicotinamid adenine dinucleotide
NADR=H
R=Phosphate: NADP+, NADPH
N
N N
N
NH2
O
OHHO
HO
Adenine(Vit. B4)
N
CO2H
Nicotinic acid / Niacin(Vit. B3)
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Flavinmonooxygenase-FMO
N
N
N
NHH3C
H3C
O
OR
H2O
N
HN
N
NHH3C
H3C
O
OR
OH
N
HN
N
NHH3C
H3C
O
OR
OOH
FAD
Substrate Substrate-O
N
HN
NH
NHH3C
H3C
O
OR
FADH2
O2
NADPH
NADP+
RO
OH
NuPeroxidePeracid
O Nu
N-oxideSulfoxide
+ ROH
•Amine: ox. to N-oxide / hydroxylamine
•Sulfide: ox to sulfoxide , furter to sulfone
•Thiol:
Ox of soft Nu
R-SH R-S-S-R R-S-S-R
O
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Non-microsomal enzymes•Enzymes in mitokondria•Enzymes in soubile tissue fractions
R-OH
prim or sec.
Alchohol dehydrogenase(NAD cont.)
aldehyde / ketoneR
O
H
Aldehyde dehydrogenaseR
O
OH
Alcohol dehydrogenase Aldehyde dehydrogenaseCH3OH HCO2HCH2O
SlowEtOH cometitive substr.
rel. fast
Tox. effects:AcidosisBlindness
HN
NH
NH
HN
O
O
NH
Tetrahydrofolate
NH
O CO2H
CO2H
HN
NH
NH
HN
O
O
N
NH
O CO2H
CO2H
OH
HCO2H
Dietary folic acid
10-Formyl-THF dehydrogenase
CO2
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Non-microsomal enzymes (Phase 1)
Molybdenum Hydroxylases•Aldehyde oxidase•Xantine oxidase•Xantine dehydrogenase
Xanthine oxidaseElectron transfer: FAD - Fe2S2ˇI - Fe2S2ˇII - Moco - Substrate
Active form
Cont. Mo in cat. siteCont FAD and 2 Fe/s clustersUse H2O not O2
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•Aldehyde oxidase
R H
O
R OH
O
N
Aza heterocycle
N OH NH
O
N
N N
N
H2N
AcO
AcO
FamciclovirAntiviral (Herpes etc)Pro-drug
Aldehyde oxidaseEsterase / hydrolysis HN
N N
N
H2N
HO
HO
O
Penciclovir
•Xantine oxidase•Xantine dehydrogenase
(requires NAD+)
xanthine oxidoreductase
HN
N
O
NH
N
Hypoxanthine
HN
NH
O
NH
N
Xanthine
O
HN
NH
O
NH
HN
Uric acid
OO
HN
N
O
NH
N
Allopurinol
HN
NH
O
NH
N
AlloxanthineInhib. enzyme
O
Treatment of gout (podagra)
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Non-microsomal enzymes (Phase 1)
Oxidative deamination of amines•Monoamine oxidase (MAO)•Diamine oxidase (DAO)
R-CH2-NH2 + O2 [R-CH=NH] R-CHO + NH4+
NH
NH2
HO
Serotonin5-Hydroksotryptamin (5-HT)
MAO
NH
O
HO
Serotonine: •Neurotransmittor; temp. control, mood•Depresion: Low serotonine activity•MAO Inhibitors - Older antidepresants(low selectivity)
N NH
O O
Cl
MoklobemidAurorix® Moklobemid®
Other MAO substrates:
HN
OH
HO
HOH
Noradrenaline
NH2HO
HODopamine
Not MAO substrates (subst at α-C):
NH2
(S)-amfetaminLow dopamine conc. ≈ Parkinston
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Active transport re-uptake transmittor(not Acetylcholine)
Non-selective monoamine re-uptake inhib.Tricyclic antidepressants
SSRI (selective serotonine re-uptake inhib.)“Lykkepiller” Prozac etc (Fontex)
NH2HO
HO
NH2HO
HO
OH
DA NE
HO
NH
NH2
5-HTα
β
β-Arylaminer
Y
X
RZ
N
αβ
β-Arylam
≈ β-Arylamin
Stor gruppe / sterisk hindingHindrer reopptak
O
F3C
NHH2N
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Non-microsomal enzymes (Phase 1)
Oxidative deamination of amines•Monoamine oxidase (MAO)•Diamine oxidase (DAO)
Oxidize diamines, histamine NH2
HN
N
MAO like enzymes in plants
N
N NH
N
HN
BAPCYtokinin (Plant growth hormone)
N
N NH
N
NH2
O
+N
N NH
N N
N NH
N N
N NH
N
CK analogs, Anders Bråthe
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Non-microsomal enzymes (Phase 1)
Miscellaneous react.
ReductionsS S RR R-SH
R-SO-R R-S-R (i.e.DMSO)
R-CO-R R-CHOH-R
R-NO-R R-NH-R
R-CH=CH-R R-CH2-CH2-R
R-OH R-H
Ar-OH Ar-H
β-Oxidation
R-CH2-CH2-CO2H R-CH2-CH2-CO-S-CoA R-CO2H
+
CHa-CO-S-CoA
Acetyl-CoA
R-CO-S-CoA
N
N N
N
NH2
O
OHPO3
OP
OP
O
HN
O OO OOH
O
HN
S
O
O
Acetyl-CoA
Nu
Hydrolysis - Esterases
O
ORR'
O
NRR'
R''
O
OHR
Esters as pro-drugs
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Pathways of metabolism
Phase 1: Biotransformation
Attachment of new functional groups, transformation of exist. funct. groups
oxidation, reduction, hydroxylation, hydrolysis etc.
Phase 2: Conjugation.
Masking of an exist. funct. group by for instance
acetylation, glycosylation, attachment amino acid etc
More hydrophilic drug
Renal excretion
O OHHO
NCH3
Morphine
Demethylation
Phase 1 O OHHO
NH
Conjugationglucuronic acid
Phase 2 O OHO
NH
O OHCO2H
OHHO
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Phase 2: Conjugation
Most comp. excreted as cojugates, ionic, hydrophilic groups added,
most common glucuronation
•Glucuronic acid conjugation•Sulfate conjugation•Conjugation with amino acids•Acetylation•Glutathione conjugation•Methylation
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Phase 2: Conjugation
•Glucuronic acid conjugation
Substrates:
•Alchohols
•Phenols
•Amines
•Sulfides
•Carboxylic acids
•1,3-Dicarbonyls
O
HO
OHOHOH
OH
Glucose
O
CO2H
OHOOH
OH
UDP-Glucuronate
P P O
HO OH
N
N
O
O
RXH
O
CO2H
OHOH
OH
XR
RXH: Xenobiotic / Phase 1 metabolite
O
CO2H
OHOH
OH
XR
Kidney Urive excretion
Bile (galle)
RXH
O
CO2H
OHOH
OH
XR
IntestineRXH
Poor reabsorb.
O
CO2H
OHOH
OH
XR
Reabsorb
Entro-hepatic recyclingImportant for many hormones etc
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O
CO2H
OHOOH
OH
UDP-Glucuronate
P P Uridine
OH
O
CO2H
OHOH
OH
OR
O
R
O
Relatively labile
Hydrolysis
OH R
O
HNu Macromolecule
Nu MacromoleculeR
O
Altered protein (hapten)Unwanted immune responce / allergic react.
Acyl migr.
ex. NSAIDs
Ar-NH2
Phase 1Ar-NH-OH Ar-NH-OH-Glu
UrinepH<7
Ar-NH-OH
H2O
Ar-N
Nitrene(c.f. carbene)
Bladder cancer
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Phase 2: Conjugation
•Sulfate conjugation: Phenols, (alcohols, N-compounds)
ATPO NPO
O
OH
S
O
O
O
HO3P OH
PAPS
N
N
N
NH2HO
OS
O
O
O
•Conjugation with amino acids (Most ofthen Gly): Carboxylic acids
R-CO2H
O
R SCoA
H2N CO2H O
R NH
CO2H
No tox. conjugates known
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Phase 2: Conjugation •Acetylation: N-compounds
O
H3C SCoANH N
O
•Glutathione conjugation: Electrophilic species
HS NH
HN
O CO2H
O
NH2
CO2HR-X + S NH
HN
O CO2H
O
NH2
CO2H
R
Glutathione conjugate
S OH
HN
O
O
R
Mercapturic acid der.
•Alkylhalides•Epoxides•Michael acceptors etc
may otherwisealkylate biomolecules
Br
BrRSH
Br
S
S R
Nu(i.e. DNA)
HN
O
OH
Paracetamol
Phase 1CYP450
H2O
N
O
O
HS-R
O
HN
O
SRH
HN
O
OH
SR
H2N Liver Protein
Liver dammage
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Phase 2: Conjugation •Methylation (O and N- compd)
Prod. may be more lipophilic
React. mainly aimed at converting endogenic compouds
O.Metylation by COMT (catecol O-methyl transferase)
ATPO N
HO OH
N
N
N
NH2HO
OH3C
SAM (S-adenocyl methionine)
SH3C
CO2HH2N
HO
HO
SAM may also methylate N-comp.
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HO
HO
OH
NH2
Noradrenaline(Norepinephrine)
MAO
HO
HO
OH
CHOAldehyde Dehydrogenase
HO
HO
OH
CO2H
COMT
HO
H3CO
OH
NH2
COMT
HO
H3CO
OH
CO2HMAO Aldehyde
Dehydrogenase
OH
NH2
EphedrineAdrenerg agonist
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Conjugation react, in plant metabolism
N
N NH
N
HN
t-ZeatinCytokinin (Plant growth hormone)
N
N NH
N
NH2
OH
MAO likeenzynme
Not reversible, permanent inactivation
N
N NH
N
HN
OGlu
N
N N
N
HN
OH
Inactive storage forms
(Glu = Glucose)
N
N N
N
HN
OH
NH2
CO2H
alanine
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