Cst125 Slide Biotransformasi

8/12/2019 Cst125 Slide Biotransformasi

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,

. ,Fakultas Kedokteran

n vers tas umatera tara25 Januari 2008, KBK, FK USU


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Pharmacokinetic

o absorption

o distribution

o elimination


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Elimination

Drug MetabolismExcretion


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The chemical modification of drugs with

e overa goa o ge ng r o e rug change ze

lipid solubility

Enzymes are typically involved in

DrugMetabolism

More polar Excretion

(water soluble)

Drug


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-

- Oxidation : Morphin,

- Reduction : Chloramphenicol,onazepam

- Hydrolisis : Aspirin, Lidocain


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-

- Conjugation : Morphin

process g ucoror at on ,

INH (process acetilation),etc.


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PENGARUH FPE TERHADAP BIO-AVAILABILITY ( KETERSEDIAAN BIOLOGIS)

BA : %ase obat yang secara utuh mencapai sirkulasi umum untuk melakukan kerjanya

proses absorpsi

-

FPE di hati

REAKSI TRANSFORMASIPEROMBAKAN PENGGABUNGAN/KONJUGASI

OKSIDASI:

- Enzim oksidatif : sitokromP450(CYP450)

- Alkohol,aldehide, asam dan zat hidrat arang

ASETILASI :

- Asam cuka mengikat gugus amino yang tak dapat

Molekul obat bergabung dengan molekul yang terdapat

dalam tubuh sambil mengeluarkan air

dioksidasi menjadi CO2 dan air

REDUKSI:

- Kloralhidrat direduksi menjadi trikloretanol

, .

SULFATASI :

- Asam sulfat mengikat gugus OH fenolis menjadi ester,

mis. Estron (sulfat)

- Vitamin C menjadi dehidroaskorbat

HIDROLISA:

Molekul obat mengikat 1 molekul air dan

ecah men adi 2 ba ian

GLUKURONIDASI :

- Asam glukoronat membentuk glukuronida dengan cara

mengikat gugus-OH (fenolis) pula (morfin, kamfer,dsb)

dan trikloretanol

-Penyabunan ester oleh esterase

- Gula oleh karbohidrase

METILASI:

- Molekul obat bergabung dengan gugus-CH3, misalnya

nikotinamid dan adrenalin menjadi derivat metilnya.


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E.g. brain, kidney, lung

ut most y n t e ver ecause

all of the blood in the body passes throughthe liver.


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Conse uences OfMetabolism

Drug metabolism ! = Drug inactivation

e me a o e may ave

Equal activity to the drug No orreduced activity

Increased activity (Prodrugs)

Toxic properties, not seen with the parentdrug


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Microsomal cytochrome P450monooxygenase family of enzymes, which

oxidize drugs

Act on structurall unrelated dru s

Metabolize the widest range of

.


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note: hi h clearance dru have > 30% extraction

from hepatic blood (F < 0.7) a drug that inhibits hepatic metabolism will

e e v y e e u(provided it is metabolised by the enzyme(s)

inhibited and vice-versa Examples:

cimetidine inhibits CYP450s, therefore doubles oral

phenytoin induces enzymes, therefore decreasesfelodipine bioavailability

,

amitrptiline bioavailability is higher


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Enzyme Inhibition and Inactivation

Enzyme Inhibitorcompound that slows or blocks enzyme catalysis

Why inhibit an enzyme?

Enzyme substrate beneficial (essential), but depleted

low levels of GABA lead to seizurestherefore inhibit

Enzyme product harmful

oxidase prevents conversion of xanthine to uric acid


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inhibit metabolism of high clearancedrugs)

if this metabolic route is a major pathway,(increase Css and T(1/2)) and thereforedrug response will change

enzyme inhibition is immediate, and on

is immediate


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Reversible Enz me InhibitorsKD Ki

Ki = koff / kon therefore smaller Ki = better inhibitor

inhibitor binds at active site; blocks substrate binding

inhibitor may be metabolized eas er o es gn

non-competitive inhibitor

binds at different (allosteric) site

changes enzyme conformation to prevent binding or turnover

difficult to design


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Drug molecule (or a portion thereof) becomes

irreversibly (covalently) bound to enzyme

Reactive compound similar to natural enzyme substrate

Reacts with nucleo hile in active site: ac lation, alk lation

Enzyme selectivity

Binding specificity


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examples with regards to enzymes other

an cy oc rome s

examp e : a opur no

is a xanthine oxidase inhibitor (used as an

-

also inhibits metabolism of cytotoxic agent

6-mercaptopurine (6-MP) therefore concurrent use of allopurinol and

6-MP leads to elevated plasma levels of 6-

example 2: disulfiram

inhibits aldeh de deh dro enase

therefore is used to give alcoholics a nasty

"aldehyde reaction" when they take alcohol


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for high first pass clearance drugsonly, a fall in liver blood flow will

cause a clear reduction in systemic

clearanceexample: lignocaine toxicity can occur

when patients are given a beta-

blocker which reduces liver blood flow


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Intravenous

Administration

Oral

Administration

LiverMetabolism

ntest nes


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the breakdown, detoxification and removal


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pass through

reaching

undergo

me a o sm yliver


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-

Metabolism of drug by liver before drug

Drug absorbed into portal circulation, mustpass roug ver o reac sys em c

circulation

May reduce availability of drug


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Factors Affecting

Biotransformation


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Factors influencing drug

biotransformation

Pregnancy

sease

Genetics


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less developed enzyme system

very old decreased I absorption

decreased renal clearance


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liver disease

some may increase

o er seases a ecrease ver

enzymes

hypothyroid hypoxemia

malnutrition


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genetic alterations or defects in

enzymes

metabolize drug more slowly or more

rapidly


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-

liverliver

bilebilebloodblood


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-

lipid soluble drugs have prolonged effects


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decreased rate of biotransformation


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.

if drugs lower doses

meta o sm rap y.

2.Zerro order kineticif drugs higher doses

.


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Cst125 Slide Biotransformasi

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