BIOTRANSFORMASIBIOTRANSFORMASI

Aznan Lelo Tri WidyawatiAznan Lelo, Tri WidyawatiDep Farmakologi & TerapeutikDep. Farmakologi & Terapeutik,

Fakultas KedokteranU i it S t UtUniversitas Sumatera Utara

25 Januari 2008, KBK, FK USU

Pharmacokinetic

o absorption o distribution

•BIOTRANSFORMATION•BIOTRANSFORMATIONo elimination

EliminationElimination

Elimination

Drug Metabolism (Biotransformation)

Excretion(Biotransformation)

Drug MetabolismDrug Metabolism• The chemical modification of drugs with

th ll l f tti id f th dthe overall goal of getting rid of the drug• change

si e– size – lipid solubility– charge or polaritycharge or polarity

• Enzymes are typically involved in metabolismmetabolism

DrugMetabolism More polar Excretion

(water soluble)Drug

METABOLISM REACTIONMETABOLISM REACTION• PHASE - IPHASE I

- Oxidation : Morphin, acetaminophenacetaminophen

- Reduction : Chloramphenicol,ClClonazepam

- Hydrolisis : Aspirin, Lidocain

METABOLISM REACTIONMETABOLISM REACTION

• PHASE- IIPHASE- II- Conjugation : Morphin

( l id ti )(process glucororidation),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) atau dindingnya• penguraian di dalam usus (kuman-kuman) atau dindingnya

• 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 dioksidasi mis Asetilasi dari sulfonamida dan piramidon

Molekul obat bergabung dengan molekul yang terdapat dalam tubuh sambil mengeluarkan air

dioksidasi menjadi CO2 dan air

• REDUKSI:

- Kloralhidrat direduksi menjadi trikloretanol

dioksidasi, mis. Asetilasi dari sulfonamida dan piramidon

• SULFATASI :

- Asam sulfat mengikat gugus OH fenolis menjadi ester, mis. Estron (sulfat)

- Vitamin C menjadi dehidroaskorbat

• HIDROLISA:

Molekul obat mengikat 1 molekul air dan pecah menjadi 2 bagian

• GLUKURONIDASI :

- Asam glukoronat membentuk glukuronida dengan cara mengikat gugus-OH (fenolis) pula (morfin, kamfer,dsb) dan trikloretanolpecah menjadi 2 bagian

-Penyabunan ester oleh esterase

- Gula oleh karbohidrase

dan trikloretanol

• METILASI:

- Molekul obat bergabung dengan gugus-CH3, misalnya nikotinamid dan adrenalin menjadi derivat metilnya.

Sites of Drug MetabolismSites of Drug Metabolism

• Metabolism occurs in many tissues• Metabolism occurs in many tissues–E.g. brain, kidney, lung

B t tl i th li b• But mostly in the liver because …all of the blood in the body passes through the liver.

Consequences Of Co seque ces OMetabolism

• Drug metabolism ! = Drug inactivationThe metabolite ma ha e• The metabolite may have

Equal activity to the drugNo or reduced activityIncreased activity (Prodrugs)Toxic properties, not seen with the parent drug

The Most Important EnzymesThe Most Important Enzymes

• Microsomal cytochrome P450 monooxygenase family of enzymes, which oxidize drugs

• Act on structurally unrelated drugsy g• Metabolize the widest range of

drugsdrugs.

Alteration in “first pass metabolismAlteration in first pass metabolism

• note: high clearance drug have > 30% extraction g g %from hepatic blood (F < 0.7)

• a drug that inhibits hepatic metabolism will increase bioa ailabilit of high clearance dr gincrease bioavailability of high clearance drug (provided it is metabolised by the enzyme(s) inhibited) and vice-versa)

• Examples:– cimetidine inhibits CYP450s, therefore doubles oral

propranolol bioavailabilitypropranolol bioavailability – phenytoin induces enzymes, therefore decreases

felodipine bioavailability acute alcohol intake inhibits a CYP therefore– acute alcohol intake inhibits a CYP, therefore amitrptiline bioavailability is higher

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 seizures—therefore inhibit GABA aminotransferase to prevent degradation of GABAGABA aminotransferase to prevent degradation of GABA

• Enzyme product harmfulexcess uric acid leads to gout—inhibition of xanthineexcess uric acid leads to gout inhibition of xanthine oxidase prevents conversion of xanthine to uric acid

Enzyme InhibitionEnzyme Inhibition(drugs that reduce hepatic blood flow also–(drugs that reduce hepatic blood flow also inhibit metabolism of high clearance drugs)

–if this metabolic route is a major pathway of elimination drug kinetics will changeof 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 normalcessation of inhibitor, reversion to normal is immediate

Reversible Enzyme Inhibitorsy

E +E • S SKD

+ I E • IKi

• Ki = koff / kon therefore smaller Ki = better inhibitor

competitive inhibitor

E +E • S S + I E • I

competitive inhibitor• inhibitor binds at active site; blocks substrate binding• inhibitor may be metabolized

i t d i• easier to designnon-competitive inhibitor• binds at different (allosteric) site• changes enzyme conformation to prevent binding or turnover• difficult to design

Irreversible Enzyme InhibitorsIrreversible Enzyme InhibitorsDrug molecule (or a portion thereof) becomes g ( p )

irreversibly (covalently) bound to enzyme

• Affinity labeling agentAffinity labeling agent– Reactive compound similar to natural enzyme substrate– Reacts with nucleophile in active site: acylation, alkylationp y , y

Enzyme selectivity

Binding specificity

examples with regards to enzymes other th t h P450than cytochrome P450s

l 1 ll i l– example 1: allopurinol » is a xanthine oxidase inhibitor (used as an

anti-gout agent)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 6-MP and toxicityMP and toxicity

– example 2: disulfiram » inhibits aldehyde dehydrogenase y y g» therefore is used to give alcoholics a nasty

"aldehyde reaction" when they take alcohol

Alteration of liver blood flow: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 beta-blocker which reduces liver blood flow

IntravenousAdministration

Oral Administration

LiverMetabolism

I t tiIntestines

Drug biotransformationDrug biotransformation

The process of drug metabolism involvingThe process of drug metabolism involving the breakdown, detoxification and removal

of chemicals from the bodyof chemicals from the body

Drug biotransformationDrug biotransformation

• Liver is primary site of drug metabolismLiver is primary site of drug metabolism• Oxidation: drug conversion to more water

soluble compoundsoluble compound• Iso-enzymes• Metabolite formation

First Pass EffectFirst Pass Effect

• pass through liver beforeliver before reaching circulationcirculation

• undergo metabolism bmetabolism by liver

Hepatic ‘First-Pass’ MetabolismHepatic First Pass Metabolism

• Affects orally administered drugsAffects orally administered drugs• Metabolism of drug by liver before drug

reaches systemic circulationreaches systemic circulation• Drug absorbed into portal circulation, must

th h li t h t ipass through liver to reach systemic circulation

• May reduce availability of drug

Factors Affecting Biotransformation

Factors influencing drug biotransformation

• AgeAge• Pregnancy

Di• Disease• Genetics

AgeAge• very youngvery young

– less developed enzyme systemless developed blood brain barrier– less developed blood brain barrier

• very oldG– decreased GI absorption

– decreased renal clearance

DiseaseDisease• altered liver enzymesaltered liver enzymes

– liver disease• most decrease enzymes• most decrease enzymes• some may increase

th di th t d d li• other diseases that decreased liver enzymes– hypothyroid – hypoxemia– malnutrition

OtherOther

• genetic alterations or defects in enzymes– metabolize drug more slowly or more

rapidly

GI: Biliary-Fecal RouteGI: Biliary Fecal Route

liverliver

bilebilebloodblood

gall bladdergall bladder

b oodb ood

gall bladdergall bladder

GI trackGI trackGI trackGI track

GI: Biliary-Fecal RouteGI: Biliary Fecal Route

• lipid soluble drugs have prolonged effects

Decreased Activity of Liver EnzymesDecreased Activity of Liver Enzymes

• decreased rate of biotransformation

can result in toxic effectscan result in toxic effects

METABOLISM KINETICMETABOLISM KINETIC

• 1 First order kinetic1.First order kineticif drugs lower doses

t b li idlmetabolism rapidly.• 2.Zerro order kinetic

if drugs higher doses metabolism slowlymetabolism slowly.

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