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BIOTRANSFORMASI
Aznan Lelo
Lelo, Tri Widyawati
Dep Farmakologi & Terapeutik
Dep.
Terapeutik,
Fakultas Kedokteran
U i
Universitas
it Sumatera
S
t
Utara
Ut
25 Januari 2008, KBK, FK USU
Pharmacokinetic
o absorption
o distribution
•BIOTRANSFORMATION
o elimination
Elimination
Elimination
Excretion
Drug Metabolism
(Biotransformation)
Drug Metabolism
• The chemical modification of drugs with
th overallll goall off getting
the
tti rid
id off th
the d
drug
• change
– size
si e
– lipid solubility
– charge or polarity
• Enzymes are typically involved in
metabolism
Drug
Metabolism
More polar
(water soluble)
Drug
Excretion
METABOLISM REACTION
• PHASE - I
- Oxidation : Morphin,
acetaminophen
- Reduction : Chloramphenicol,
Clonazepam
Cl
- Hydrolisis : Aspirin, Lidocain
METABOLISM REACTION
• PHASE- II
- Conjugation : Morphin
(
(process
glucororidation),
l
id ti )
INH (process acetilation),
etc.
PENGARUH FPE TERHADAP BIO-AVAILABILITY ( KETERSEDIAAN BIOLOGIS)
• BA : %ase obat yang secara utuh mencapai sirkulasi umum untuk melakukan kerjanya
• proses absorpsi
• penguraian di dalam usus (kuman
(kuman-kuman)
kuman) atau dindingnya
• FPE di hati
PEROMBAKAN
REAKSI TRANSFORMASI
• OKSIDASI:
- Enzim oksidatif : sitokromP450(CYP450)
- Alkohol,aldehide, asam dan zat hidrat arang
dioksidasi menjadi CO2 dan air
• REDUKSI:
- Kloralhidrat direduksi menjadi trikloretanol
- Vitamin C menjadi dehidroaskorbat
• HIDROLISA:
PENGGABUNGAN/KONJUGASI
Molekul obat bergabung dengan molekul yang terdapat
dalam tubuh sambil mengeluarkan air
• ASETILASI :
- Asam cuka mengikat gugus amino yang tak dapat
dioksidasi mis
dioksidasi,
mis. Asetilasi dari sulfonamida dan piramidon
• SULFATASI :
- Asam sulfat mengikat gugus OH fenolis menjadi ester,
mis. Estron (sulfat)
• GLUKURONIDASI :
Molekul obat mengikat 1 molekul air dan
pecah menjadi 2 bagian
- Asam glukoronat membentuk glukuronida dengan cara
mengikat gugus-OH (fenolis) pula (morfin, kamfer,dsb)
dan trikloretanol
-Penyabunan ester oleh esterase
• METILASI:
- Gula oleh karbohidrase
- Molekul obat bergabung dengan gugus-CH3, misalnya
nikotinamid dan adrenalin menjadi derivat metilnya.
Sites of Drug Metabolism
• Metabolism occurs in many tissues
– E.g. brain, kidney, lung
• But
B t mostly
tl in
i th
the liver
li
b
because
…
all of the blood in the body passes through
the liver.
Consequences
Co
seque ces O
Of
Metabolism
• Drug metabolism ! = Drug inactivation
• The metabolite ma
may ha
have
e
ƒ
ƒ
ƒ
ƒ
Equal activity to the drug
No or reduced activity
Increased activity (Prodrugs)
Toxic properties, not seen with the parent
drug
The Most Important Enzymes
• Microsomal cytochrome P450
monooxygenase family of enzymes, which
oxidize drugs
• Act on structurally
y unrelated drugs
g
• Metabolize the widest range of
drugs.
drugs
Alteration in “first
first pass metabolism
• note: high
g clearance drug
g have > 30%
% extraction
from hepatic blood (F < 0.7)
• a drug that inhibits hepatic metabolism will
increase bioa
bioavailability
ailabilit of high clearance dr
drug
g
(provided it is metabolised by the enzyme(s)
inhibited)) and vice-versa
• Examples:
– cimetidine inhibits CYP450s, therefore doubles oral
propranolol bioavailability
– phenytoin induces enzymes, therefore decreases
felodipine bioavailability
– acute alcohol intake inhibits a CYP
CYP, therefore
amitrptiline bioavailability is higher
Enzyme Inhibition and Inactivation
Enzyme Inhibitor
compound that slows or blocks enzyme catalysis
Why inhibit an enzyme?
• Enzyme substrate beneficial (essential), but depleted
low levels of GABA lead to seizures—therefore inhibit
GABA aminotransferase to prevent degradation of GABA
• Enzyme product harmful
excess uric acid leads to gout—inhibition
gout inhibition of xanthine
oxidase prevents conversion of xanthine to uric acid
Enzyme Inhibition
–(drugs
(drugs that reduce hepatic blood flow also
inhibit metabolism of high clearance
drugs)
–if this metabolic route is a major pathway
of elimination
elimination, drug kinetics will change
(increase Css and T(1/2)) and therefore
drug response will change
–enzyme inhibition is immediate, and on
cessation of inhibitor, reversion to normal
is immediate
Reversible Enzyme
y
Inhibitors
Ki
KD
E•S
•
E + S +
I
E•I
Ki = koff / kon therefore smaller Ki = better inhibitor
competitive inhibitor
• inhibitor binds at active site; blocks substrate binding
• inhibitor may be metabolized
• easier
i tto design
d i
non-competitive inhibitor
• binds at different (allosteric) site
• changes enzyme conformation to prevent binding or turnover
• difficult to design
Irreversible Enzyme Inhibitors
Drug
g molecule ((or a p
portion thereof)) becomes
irreversibly (covalently) bound to enzyme
• Affinity labeling agent
– Reactive compound similar to natural enzyme substrate
– Reacts with nucleophile
p
in active site: acylation,
y
, alkylation
y
Enzyme selectivity
Binding specificity
examples with regards to enzymes other
th cytochrome
than
t h
P450
P450s
– example
l 1
1: allopurinol
ll
i l
» is a xanthine oxidase inhibitor (used as an
anti-gout
anti
gout agent)
» also inhibits metabolism of cytotoxic agent
6-mercaptopurine (6-MP)
» therefore concurrent use of allopurinol and
6-MP leads to elevated plasma levels of 6MP and toxicity
– example 2: disulfiram
y dehydrogenase
y g
» inhibits aldehyde
» therefore is used to give alcoholics a nasty
"aldehyde reaction" when they take alcohol
Alteration of liver blood flow:
–for high first pass clearance drugs
only, a fall in liver blood flow will
cause a clear reduction in systemic
clearance
–example: lignocaine toxicity can occur
when patients are given a betablocker which reduces liver blood flow
Intravenous
Administration
Oral
Administration
Metabolism
Liver
I t ti
Intestines
Drug biotransformation
The process of drug metabolism involving
the breakdown, detoxification and removal
of chemicals from the body
Drug biotransformation
• Liver is primary site of drug metabolism
• Oxidation: drug conversion to more water
soluble compound
• Iso-enzymes
• Metabolite formation
First Pass Effect
• pass through
liver before
reaching
circulation
• undergo
metabolism b
by
liver
Hepatic ‘First-Pass’
First Pass Metabolism
• Affects orally administered drugs
• Metabolism of drug by liver before drug
reaches systemic circulation
• Drug absorbed into portal circulation, must
pass through
th
h liliver tto reach
h systemic
t i
circulation
• May reduce availability of drug
Factors Affecting
Biotransformation
Factors influencing drug
biotransformation
•
•
•
•
Age
Pregnancy
Di
Disease
Genetics
Age
• very young
– less developed enzyme system
– less developed blood brain barrier
• very old
– decreased GI
G absorption
– decreased renal clearance
Disease
• altered liver enzymes
– liver disease
• most decrease enzymes
• some may increase
• other
th di
diseases th
thatt d
decreased
d liliver
enzymes
– hypothyroid
– hypoxemia
– malnutrition
Other
• genetic alterations or defects in
enzymes
– metabolize drug more slowly or more
rapidly
GI: Biliary
Biliary-Fecal
Fecal Route
liver
blood
b
ood
bile
gall bladder
GI track
GI: Biliary
Biliary-Fecal
Fecal Route
• lipid soluble drugs have prolonged effects
Decreased Activity of Liver Enzymes
• decreased rate of biotransformation
can result in toxic effects
METABOLISM KINETIC
• 1
1.First
First order kinetic
if drugs lower doses Æ
metabolism
t b li
rapidly.
idl
• 2.Zerro order kinetic
if drugs higher doses Æ
metabolism slowly
slowly.
Dosis Obat
Keceepatan Meetabolism
me obat