METABOLISME

Zita Dhirani P.
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Metabolisme/ Biotransformasi

◎ Proses berubahnya obat utuh (senyawa induk) oleh

sistem enzim tertentu di dalam makhluk hidup,
menjadi metabolit yang secara kimia berbeda dengan
senyawa induk

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Metabolisme

◎ Prisip proses metabolisme : this process entails a loss

of biological activity and an increase in
hydrophilicity (water solubility), thereby promoting
elimination via the renal route.
◎ Tujuan metabolisme : menginaktifkan obat oleh
enzim-enzim hati dan kemudian diubah atau
ditransformasikan menjadi metabolit inaktif untuk
diekskresikan.

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Metabolisme/ Biotransformasi

◎ Drug metabolism involves two kinds of reaction, known

as phase 1 and phase 2, which often occur sequentially.
Both phases decrease lipid solubility, thus increasing
renal elimination.
◎ 2 kemungkinan
- Sarana penirkhasiatan (bioinaktivasi)/(detoksifikasi)
- Sarana pembangkitan kekhasiatan (bioaktivasi)

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Struktur Vena Porta Hepatika

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Perjalanan Metabolisme/Biotransformasi Obat

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First Pass Metabolism

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First Pass Metabolism
Obat yang digunakan secara oral akan melalui liver/hepar sebelum masuk ke
dalam darah menuju ke daerah lain dari tubuh (mis. otak, jantung, paru-paru)

Obat dapat dimetabolisme melalui beberapa cara:

- Menjadi metabolit inaktif kemudian diekskresikan
- Menjadi metabolit aktif  memiliki kerja farmakologi tersendiri bisa
dimetabolisme lanjutan
- Beberapa obat diberikan dalam bentuk tidak aktif kemudian setelah
dimetabolisme baru menjadi aktif (=prodrugs)
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Phases of Drug
Metabolism

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Phase 1

◎ Phase I reactions usually convert the parent drug to a more

polar metabolite by introducing or unmasking a functional
group (-OH, -NH2, -SH). Often these metabolites are inactive,
although in some instances activity is only modified or even
enhanced.
◎ Reaksi yang terjadi :
- Oksidasi
- Reduksi
- Hidrolisis
◎ Sistem enzim utama: aneka jenis sitokrom P450 mikrosoma.
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Classification Enzymes (Phase 1)
Oxidation Cytochrome P450
Flavin-containing monooxygenase
Alcohol dehydrogenase
Aldehyde dehydrogenase
Monoamine oxidase
H2O2-dependent peroxidase
Reduction Cytochrome P450
NADPH-P450 reductase
Carbonyl reductase
Hydrolysis Epoxide hydrolase
Carbonylesterarse/amidase
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 Phase 1

◎ Seventy-four CYP gene

families have been
described, of which
three main ones (CYP1,
CYP2 and CYP3) are
involved in drug
metabolism in human
liver.

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Phase 2

◎ Couples group to existing (or phase I formed) conjugation site

(-OH, -COOH, -NH2).
◎ Reaksi utama yang terjadi  reaksi konjugasi :
○ Glukoronidasi
○ Sulfatasi
○ Glutationasi
◎ Metabolit tend to be less lipid soluble and therefore better
excreted (less well reabsorbed).

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Classification Enzymes (Phase 2)
Conjugation UDP-glucuronosyltransferase
Sulfotransferase
Glutathion S-transferase
Mercapturic acid biosynthesis
Cysteine conjugate β-
lyase/thiomethilase
N-Acetyltransferase
N-Methyltransferase
O-Methyltransferase

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Inhibisi Enzim

◎ Certain drug substrates inhibit cytochrome P450 enzyme

activity. Imidazole-containing drugs such as cimetidine and
ketoconazole bind tightly to the P450 heme iron and
effectively reduce the metabolism of endogenous
substrates (eg, testosterone) or other coadministered
drugs through competitive inhibition.

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Inhibisi Enzim

◎ Some substrates irreversibly inhibit P450s via covalent

interaction of a metabolically generated reactive
intermediate that may react with the P450 apoprotein or
heme moiety or even cause the heme to fragment and
irreversibly modify the apoprotein. The antibiotic
chloramphenicol is metabolized by CYP2B1 to a species
that modifies the P450 protein and thus also inactivates the
enzyme.

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Inhibisi pada Prodrug

◎ When a drug works through an active metabolite,

inhibition of its metabolism can result in loss of activity.
◎ Clopidogrel works through an active metabolite formed by
CYP2C19 which is inhibited by omeprazole which might
thereby reduce the antiplatelet effect. It is unclear how
clinically important this may be, but the Food and Drug
Administration has warned against concomitant use of
these drugs for this reason.

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Induksi Enzim

◎ Some of the chemically dissimilar P450 substrate drugs, on

repeated administration, induce P450 by enhancing the
rate of its synthesis or reducing its rate of degradation.
◎ Induction results in an acceleration of substrate
metabolism and usually in a decrease in the pharmacologic
action of the inducer and also of coadministered drugs.

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Induksi Enzim

◎ However, in the case of drugs metabolically transformed to

reactive metabolites, enzyme induction may exacerbate
metabolite-mediated toxicity.
◎ Environmental pollutants are also capable of inducing P450
enzymes. As noted above, exposure to benzo[a]pyrene and
other polycyclic aromatic hydrocarbons, which are present
in tobacco smoke, charcoal-broiled meat, and other
organic pyrolysis products, is known to induce CYP1A
enzymes and to alter the rates of drug metabolism.
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Faktor Makanan

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Faktor Genetik

◎ Reaksi metabolisme case II:

asetilasi.
◎ Contoh: Isoniazid (INH) obat
TB.
◎ INH is metabolized in the
liver via acetylation.
◎ There are two forms (slow &
fast) of the enzyme N-acetyl
transferase.
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 Faktor genetik/ keturunan

Metabolisme isoniazid (OAT) melalui proses N asetilasi, proses:

pemindahan gugus asetil yang dikatalisis oleh N asetil transferase .
Studi terhadap kecepatan asetilasi :
◎ orang jepang dan eskimo : asetilator cepat (T1/2: 45-80 menit) 
tingkatkan dosis
◎ Orang eropa timur dan mesir : asetilator lambat (T1/2: 140-200
menit) monitor efek samping (neuritis perifer)
Hidralazin , prokainamid , dapson  genetik mempengaruhi
kecepatan asetilasi
Fenitoin , fenilbutazon , dikumarol , nortriptilin  genetik
mempengaruhi kecepatan oksidasi 31
Prodrug

◎ Umumnya obat aktif saat diminum dan menjadi tidak aktif

saat dimetabolisme
◎ Prodrug merupakan obat yang tidak aktif dan menjadi aktif
saat dimetabolisme dan menjadi tidak aktif lg saat
menjalani metabolisme
◎ Contoh clopidogrel merupakan prodrug, obat ini tidak aktif
dan menjadi aktif setelah menjalani metabolisme oleh
enzim hepar (CYP2C19)

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Contoh Interaksi Metabolisme/Biotransformasi

◎ Penggunaan fenobarbital bersamaan dengan warfarin

◎ Penggunaan kloramfenikol bersamaan dengan
klorpropamid

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