metabolism obat.pdf
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1. Menjelaskan peran hepar dalam eliminasi obat
2. Menjelaskan klasifikasi hasil metabolisme obat
3. Menjelaskan jalur reaksi metabolisme obat dan ensim
yang terlibat4. Menjelaskan sumber variasi metabolisme obat
5. Memprediksi perubahan klirens akibat adanya interaksi
pada metabolisme obat
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Perfusi Liver:
Hepatic artery
Hepatic portal vein(vena porta)
Peranvena hepatica ?
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Peran hepar dalam
metabolisme obat ?
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Drug MetaboliteEnzyme
Metabolisme obat adalah ..............................................................
..........................................................................................................
..........................................................................................................
..........................................................................................................
......................................................................
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No Drug Metabolite
1 Active Inactive
2 Active Active
3 Inactive Active
4 Active Reactive Intermediate
Contoh
Reaksi ?
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Aciclovir:is poorly absorbed from the gastrointestinal tract after oral
dose. Bioavailability of oral aciclovir is about 10 to 20%; orally
active prodrugssuch as valciclovirhave been developed to
overcome this poor absorption.
Pertanyaan:
Bagaimana valciclovir dapat bekerja sebagai prodrugs ?
Valciclovir: is readily absorbed from the gastrointestinal tract
after oral doses, and rapidly converted to aciclovir and valine byfirst-pass intestinal or hepatic metabolism.
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Reaksi Fase I:
Reaksi fase I adalah reaksi .............................................
Tipe reaksi & ensim yang terlibat:1. ...................................................................................
2. ...................................................................................
3. ...................................................................................
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Reaksi Fase II:
Reaksi fase II adalah reaksi
...............................................
Tipe reaksi & ensim yang terlibat:
1. ......................................................................................
2. ......................................................................................
3. ......................................................................................
4. ......................................................................................
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The MFOs System
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Salicylic acidSalicylacyl
glucuronideSalicylurea
Genticyl urate GentisateSalicyl phenolic
glucuronide
Sulphates conjugates
gentisate
Glucuronide conjugates
gentisate
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http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+codeine&source=images&cd=&cad=rja&docid=4spp6u3fMzJUzM&tbnid=obfbWNt4fD3cqM:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S037907381000349X&ei=_KU_Ucj8Ea-eiAft8oC4DA&bvm=bv.43287494,d.bmk&psig=AFQjCNEYSU-qouIhjMOQJALt2nmR63LKTg&ust=1363212126143364 -
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Paracetamole is very safe provided in the normal
therapeutic dose. However after overdoses (8-10 g), fatal
liver damage can results.
Paracetamole is metabolized mainly by conjugation withsulphate and glucuronic acid ( 90-95%).
Only a minor proportion is metabolized by oxidation
which is catalysed by cytochrome P450. This producesa metabolite which is toxic but normally detoxified by
reaction with glutathione.
http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+paracetamol&source=images&cd=&cad=rja&docid=7ZAaZyhAzfgTTM&tbnid=cVBgk0Yeuzjt5M:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S1089326107000499&ei=yqM_UfauEfGwiQfeyYCQBA&bvm=bv.43287494,d.bmk&psig=AFQjCNHw-CE39cwpOOs4VG__YtNSZMz8vQ&ust=1363211587804554 -
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GSH
Reactive
intermediate
N-acetyl
systeine
Metabolisme Paracetamol
http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+paracetamol&source=images&cd=&cad=rja&docid=7ZAaZyhAzfgTTM&tbnid=cVBgk0Yeuzjt5M:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S1089326107000499&ei=yqM_UfauEfGwiQfeyYCQBA&bvm=bv.43287494,d.bmk&psig=AFQjCNHw-CE39cwpOOs4VG__YtNSZMz8vQ&ust=1363211587804554http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+paracetamol&source=images&cd=&cad=rja&docid=7ZAaZyhAzfgTTM&tbnid=cVBgk0Yeuzjt5M:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S1089326107000499&ei=yqM_UfauEfGwiQfeyYCQBA&bvm=bv.43287494,d.bmk&psig=AFQjCNHw-CE39cwpOOs4VG__YtNSZMz8vQ&ust=1363211587804554http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+paracetamol&source=images&cd=&cad=rja&docid=7ZAaZyhAzfgTTM&tbnid=cVBgk0Yeuzjt5M:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S1089326107000499&ei=yqM_UfauEfGwiQfeyYCQBA&bvm=bv.43287494,d.bmk&psig=AFQjCNHw-CE39cwpOOs4VG__YtNSZMz8vQ&ust=1363211587804554http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+paracetamol&source=images&cd=&cad=rja&docid=7ZAaZyhAzfgTTM&tbnid=cVBgk0Yeuzjt5M:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S1089326107000499&ei=yqM_UfauEfGwiQfeyYCQBA&bvm=bv.43287494,d.bmk&psig=AFQjCNHw-CE39cwpOOs4VG__YtNSZMz8vQ&ust=1363211587804554http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+paracetamol&source=images&cd=&cad=rja&docid=7ZAaZyhAzfgTTM&tbnid=cVBgk0Yeuzjt5M:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S1089326107000499&ei=yqM_UfauEfGwiQfeyYCQBA&bvm=bv.43287494,d.bmk&psig=AFQjCNHw-CE39cwpOOs4VG__YtNSZMz8vQ&ust=1363211587804554http://www.google.co.id/url?sa=i&rct=j&q=metabolism+of+paracetamol&source=images&cd=&cad=rja&docid=7ZAaZyhAzfgTTM&tbnid=cVBgk0Yeuzjt5M:&ved=0CAUQjRw&url=http://www.sciencedirect.com/science/article/pii/S1089326107000499&ei=yqM_UfauEfGwiQfeyYCQBA&bvm=bv.43287494,d.bmk&psig=AFQjCNHw-CE39cwpOOs4VG__YtNSZMz8vQ&ust=1363211587804554 -
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1. Faktor genetik
2. Kondisi fisologis
3. Faktor lingkungan & Interaksi obat4. Regimen dosis
Intrinsic
Clearance
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Variasi genetik pada cytochrome P-450 (CYP) isozymes
Kasus:
Rapid acetylatorsvs Slow acetylators pada asetilasi
isoniazide (Evans et al, 1968)
EM (Efficient Metabolizer) vs PM (Poor Metabolizer)
phenytoin pada 4% subjek caucasian & 16% subjek di
Jepang (Wilkinson et al, 1998)
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1. Usia
2. Gender
3. Diet/Nutrisi
4. Patofisiologi
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Age Metabolism Capacity Development
Birth Sulfatation
1st
week Reduction, Oxidation
1stmonth Acetylation
2ndmonth Glucuronidation
3thmonth Glycine, Glutathione, & Cystein Conjugation
Children
are not
little adults
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Rute pemberian obat
hepatic first-pass effect
Dose-dependent (non-linear)
pharmacokinetics
2
1
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1. Induksi Ensim (Inducer)
2. Inhibisi Ensim (Inhibitor)
Intrinsic Clearance
Hepar
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Inducer Induced Drugs
Carbamazepin Paracetamol; Phenytoin; Warfarin
Griseofulvin; Haloperidol;
Meprobamat*)Warfarin
Phenytoin Cortisol; Digitoxin; Phenobarbital
Phenobarbital*) Chloramphenicol; Cortisol,eDexamethazon; Digitoxin; Estradiole;
Griseofulvin; Phenytoin; Progesteron;
Testoteron; Tolbutamid
Rifampicin*)
Estrogen; Methadon; Phenobarbital;Prednisolon; Saquinavir; Warfarin
*) auto-inducer
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Inducer:
Benzopyrene(asap rokok)
Chlordane(insektisida)
3-methyl-cholantrene(polycyclic hydrocarbons)
Laju eliminasi theophylline meningkat pada perokok
induksi ensim oleh benzopyrene
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Inhibitors Inhibited Drugs
Cimetidine Phenytoine; Theophylline; Warfarine
Erythromycine Carbamazepien
Fluoxetine Imipramine; Desipramine
MeperidinePromazine
Kontrasepsi oral
Phenytoine Bishydrocoumarine; Chloramphenicole,
Cycloserine, Isoniazide, Sulpha
Tolbutamide Chloramphenicole, Phenylbutazone,
Sulpha, Probenecide, Ethanol
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Bioflavonoid:Naringin (bioflavonoid - grapefruit juice) menghambat
CYP 3A4 meningkatkan AUC Coumain, Cyclosporin,
Felodipin, Midazolam, Saquinavir etc
Penurunan intake asam lemak:
menurunkan aktivitas sistem MFO
Carbon monoxide, Heavy metals:
menghambat aktivitas ensim hepatik
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