Farmakokinetik

METABOLISME OBAT
(BIOTRANSFORMASI)
 METABOLISME Suatu proses kimia di mana
= suatu obat diubah di dalam
tubuh menjadi suatu
BIOTRANSFORMASI metabolitnya

Plasma
GI Mucosa
Nasal
passages
Lungs
Kidneys

hati
2
Sitokrom P-450 =
Cytochrom p-450

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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, jaringan lainnya)
• Di dalam liver terdapat enzim khusus (yaitu
sitokrom P450) yang akan mengubah obat
menjadi bentuk metabolitnya
• Metabolit umumnya menjadi lebih larut dalam
air (polar) dan akan dengan cepat diekskresikan
keluar tubuh (melalui urin, feses,keringat, dll.)
Hal ini akan secara dramatik mempengaruhi
kadar obat dalam plasma
• obat-obat yang mengalami first past metabolism
akan kurang bioavailabilitasnya ad efek
berkurang

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• Obat yang telah diserap oleh usus ke
dalam sirkulasi, akan diangkut
melalui sistem pembuluh porta (vena
portae), yang merupakan suplai
darah utama dari daerah lambung-
usus ke hati.
• Dengan pemberian sublingual,
transkutan, parenteral atau rektal,
sistem porta ini dan hati dapat
dihindari
• N-acetyl-p-benzoquinone imine,
merupakan hasil metabolisme yang
bersifat hepatotoksik dari
parasetamol).
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 Sites of Drug Metabolism


 Intestinal Mucosa: The extra-hepatic metabolism, contains CYP3A4 isozyme

 Isoproterenol exhibit considerable sulphate conjugation in GI tract
 Levodopa, chlorpromazine and diethylstilbestrol are also reportedly metabolized
in GI tract
 Esterases and lipases present in the intestine may be particularly important
carrying out hydrolysis of many ester prodrugs
 Bacterial flora present in the intestine and colon reduce many azo and nitro
drugs (e.g., sulfasalazine)
 Intestinal -glucuronidase can hydrolyze glucuronide conjugates excreted in the
bile, thereby liberating the free drug or its metabolite for possible reabsorption
(enterohepatic circulation or recycling)
 Drug - Drug Interactions

Risks associated with CYP enzyme inhibition or induction

Induction of CYP
Inhibition of CYP enzymes
enzymes 
Increased degradation

of comedicated drugs
Decreased degradation

of comedicated drugs
Decreased drug plasma

concentrations
Increased drug plasma

concentrations
Loss of pharmacological

effect
Risk of severe

adverse events
Risk of severe
secondary effects
• Humans have 18 families of cytochrome P450 genes and 43 subfamilies:

– CYP1 drug metabolism (3 subfamilies, 3 genes, 1 pseudogene)

– CYP2 drug and steroid metabolism (13 subfamilies, 16 genes, 16 pseudogenes)
– CYP3 drug metabolism (1 subfamily, 4 genes, 2 pseudogenes)
– CYP4 arachidonic acid or fatty acid metabolism (5 subfamilies, 11 genes, 10 pseudogenes)
– CYP5 Thromboxane A2 synthase (1 subfamily, 1 gene)
– CYP7A bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus (1 subfamily member)
– CYP7B brain specific form of 7-alpha hydroxylase (1 subfamily member)
– CYP8A prostacyclin synthase (1 subfamily member)
– CYP8B bile acid biosynthesis (1 subfamily member)
– CYP11 steroid biosynthesis (2 subfamilies, 3 genes)
– CYP17 steroid biosynthesis (1 subfamily, 1 gene) 17-alpha hydroxylase
– CYP19 steroid biosynthesis (1 subfamily, 1 gene) aromatase forms estrogen
– CYP20 Unknown function (1 subfamily, 1 gene)
– CYP21 steroid biosynthesis (1 subfamily, 1 gene, 1 pseudogene)
– CYP24 vitamin D degradation (1 subfamily, 1 gene)
– CYP26A retinoic acid hydroxylase important in development (1 subfamily member)
– CYP26B probable retinoic acid hydroxylase (1 subfamily member)
– CYP26C probabvle retinoic acid hydroxylase (1 subfamily member)
– CYP27A bile acid biosynthesis (1 subfamily member)
– CYP27B Vitamin D3 1-alpha hydroxylase activates vitamin D3 (1 subfamily member)
– CYP27C Unknown function (1 subfamily member)
– CYP39 7 alpha hydroxylation of 24 hydroxy cholesterol (1 subfamily member)
– CYP46 cholesterol 24-hydroxylase (1 subfamily member)
– CYP51 cholesterol biosynthesis (1 subfamily, 1 gene, 3 pseudogenes) lanosterol 14-alpha demethylase
Selder et all,2016
• Induction of P450 enzymes:
– PPAR (peroxisome proliferator activated receptor)
ligands (e.g.clofibrate)
– CYP1 family are induced by aromatic hydrocarbons
(cigarette smoke; charred food)
– CYP2E enzymes induced by ethanol
– CYP2B enzymes induced 40-50 fold by barbiturates

• Polymorphisms cause differences in drug metabolism:

– CYP2C19 has a polymorphism that changes the enzyme's ability to metabolize
mephenytoin (a marker drug). In Caucasians, the polymorphism for the poor
metabolizer phenotype is only seen in 3% of the population. However, it is seen in
20% of the asian population.
=> It is important to be aware of a person's race when drugs are given that are
metabolized differently by different populations

• P450s and drug interactions:

– Barbiturates induce CYP2B => increased metabolism of other drugs
– Antifungals (e.g. ketoconazole) inhibit fungal CYP51 and unintentionally also human
CYP3A4
=> reduced metabolism of other drugs
– Grapefruit juice contains a CYP3A4 inhibitor =>12 fold increase in some drug
concentrations
CYP3A4 Substrates: • Acetominophen (Tylenol) • Codeine (narcotic) •
Cyclosporin A (immunosuppressant), • Diazepam (Valium) • Erythromycin
(Antibiotic) • Lidocaine (local anaesthetic), • Lovastatin (HMGCoA reductase
inhibitor), • Taxol (cancer drug), • Warfarin (anticoagulant).
 General Metabolic Pathways
Oxidation
Hydrolytic Reactions
 Aromatic moieties
 Esters and amides
 Olefins
 Epoxides and arene oxides
 Benzylic & allylic C atoms
by epoxide hydrase
and -C of C=O and C=N
 At aliphatic and alicyclic C
 C-Heteroatom system
Phase II - Phase I - C-N (N-dealkylation, N-oxide
formation, N-hydroxylation)
Conjugation Functionalization C-O (O-dealkylation)
C-S (S-dealkylation, S-oxidation,
desulfuration)
Drug  Oxidation of alcohols and
Metabolism aldehydes
 Miscellaneous
Reduction
 Glucuronic acid conjugation  Aldehydes and ketones
 Sulfate Conjugation  Nitro and azo
 Glycine and other AA  Miscellaneous
 Glutathion or mercapturic acid
 Acetylation
 Methylation
Enzim-enzim yg terlibat pada metabolisme

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 Bioinaktivasi

Prodrug Bioaktivasi

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 1. Bioinaktif=metabolit tdk aktif
• Hidrolisis procaine menjadi p-aminobenzoic acid
and diethylethanolamine = anestetik prokain
inaktiv

• Oksidasi 6-mercaptopurine to 6-mercapturic acid = anticancer in

aktif
6-Mercaptopurine menjadi 6-Mercapturic acid (inactive)
14
 2. Bioaktivasi

Metabolites similar
Metabolites with
activity different activity

i) Codeine dimetilasi menjadi i) Iproniazid

analgesik morfin (antidepressant)
ii) Phenacetin dimetabolisme didealkilasi menjadi
isoniazid (antitubercular)
menjadi parasetamol
ii) Retinoic acid (vitamin A)
iii) Imipramine diisomerisasi menjadi
dimetilasi menjadi isoretinoic acid (anti-
antidepresan acne agent).
desipramine.
16
 3. prodrug=Bioactivated metabolites
(activation of inactive drugs):

Metabolit Efek samping

Kelebihan aktif lebih BA lebih baik &
prodrug stabil toksisitas lebih
rendah

i) Levodopa (antiparkinson disease) di didekarboksilasi di neuron menjadi dopamine

aktif

ii) prodrug sulindac (sulfoxide) NSAI direduksi menjadi sulfide aktif

iii) Benorylate menjadi aspirin and paracetamol

iv) prodrug enalapril dihidrolisi menjadi enalaprilat (potent antihypertension).

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 The Concept of Prodrugs and Antedrugs

Prodrug

M D M D activation M D M D

Antedrug

D M D M ID M
inactivation

= Barrier & ID = inactive drug, D = active drug, M = modifier

(I) Prodrug: Need metabolic activation

(II) Antedrug: Active drug that is quickly inactivated thereby minimizing systemic
effects
 What is Antedrug?

An active synthetic drug which is inactivated by a metabolic

process upon entry into the systemic circulation.
Therefore, a true antedrug acts only locally.

True Antedrug Inactive Metabolite

Partial Antedrug Less active metabolite

Lee HJ and Soliman MRI (1982). Science, 215, 989.

 Advantages of Antedrugs

M.O.F.Khan*, K.K.Park, H.J.Lee. Antedrugs: An Approach to Safer Drugs. Curr. Med. Chem., 12(19), 2227-2239, 2005.
 OCOR OH

O O

OH OH
OH
IA A
Prodrug
O
OH OH OH
OH

O O

OH OH
Antedrug
O A IA C -
CO2R O2
Hydrocortisone

(IA = Inactive Compound, A = Active Compound)

Skema biotransformasi obat

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24
Obat yg tidak dimetabolisme &
diekskresikan
Seny yg tdk larut dlm
cairan tubuh, tdk
diserap oleh
saluran cerna & tahan
thd pengaruh kimiawi BaSO4 &
enzimatik sal cerna.
Seny ini lgsg
Ol. Ricini
dikeluarkan via feses

Seny yg mdh lrt dlm

cairan tbh & tahan
thd pengaruh kimia & asam
enzimatik. Seny ini mandelat,
relatif tdk asam sulfonat
toksik & cpt dikeluarkan alifatik &
via urin aromatik
Faktor Yg Mempengaruhi
Metabolisme

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 Metabolisme presistemik
• Obat yg diberikan secara peroral bila melintasi
dinding usus & melewati hati ( sirkulasi portal)
akan mengalami metabolisme sebelum mencapai
jantung & selanjutnya mengalami sirkulasi
sistemik.
• Metabolisme obat presistemik sangat
berpengaruh terhadap ketersediaan hayati obat
• Contoh : propanolol, isoprenalin, imipramin &
lignokain
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 Bentuk stereoisomer
• Obat ------- optical aktif
• Heksobarbital (-) & warfarin (-) akan
mengalami metabolisme >>>> cepat
drpd isomer (+)

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 Stereochemistry of Drug Metabolism
Warfarin yang dimetabolisme oleh CYP2C9 menjadi bermacam -
macam turunannya yang tidak aktif secara farmakologis dan lebih
mudah larut dalam air.
OH CH2COCH3 OH CH2COCH3

Ph H
H Ph

O O O O
R-(+)-Warfarin
S-(-)-Warfarin
OH Major route Minor route OH

CH3 OH H2C H
OH CH2COCH OH H2C H CH3
HO 3 H
H
Ph
Ph Ph
H O O
O O O
R,S-(+)-alcohol derivative R,R-(+)-alcohol derivative
S-6-Hydroxywarf arin

CH3 COOH
Metabolism
H H
COOH
CH3
R-(-)-Ibuprofen
S-(+)-Ibuprofen
(inactive)
(active)
  Reaksi asetilasi merupakan p’pindahan ggs
asetil & dikatalisis enzim N-asetil transferase
 Aktivitas antituberkulosis INH sgt tgtg pd
kecepatan asetilasinya

• t ½ INH pd asetilator cpt 45-80’; pd aseilator lbt

140-200’
•Asetilator cpt ensim N-asetil transferase >>> besar
asetilator lbt • Hidralazin, prokainamid &
• Pd asetilator cpt, INH cpt diekskresikan dlm btk dapson jg mn’jukkan kcptn
asetilisoniazid yg tdk aktif, shg O memp masa kerja asetilasi yg bbeda sec genetik
pdk & butuh dosis terapi yg lbh bsr •Faktor genetik jg b’pengaruh
• Pd asetilator lbt, km’kinan tjadi efek sampng yg tdk thd kcptn oksidasi dr fenitoin,
dikhendaki,lbh bsr, mis neuritis perifer fenilbutazon, dikumarol &
•Orang Jepang & Eskimo mrpkn asetilator cepat,
nortriptilin
sedang orang Eropa timur & Mesir adalah asetilator
lambat

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 pd manusia tkonjugasi dgn glisin & glutamin; sdg pd
kelinci & tikus tkonjugasi dgn glisin saja

pd bebek diekskresikan sbg asam orniturat; sdg pd

anjing diekskresikan sbg asam hipurat

pd manusia, kelinci & marmut m’alami deaminasi

oksidatif; sdg pd tikus m’alami hidroksilasi aromatik

pd kucing tkonjugasi dgn sulfat; sdg pd babi tkonjugasi

dgn asam glukuronat, krn kucing contains lbh sdkt
enzim glukuronil transferase

pd manusia m’alami oksidasi aromatik m’hslk

S(-) parahidroksifenitoin, sdg pd anjing m’hslk
R(+)- ortohidroksifenitoin
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 . Tolbutamid, pd bayi baru lhr memp waktu paro ± 40 jam; sdg pd
org dws ± 8 jam. Hal ini disebabkan kemampuan bayi utk mtblsm
oksidatif msh rdh
• Kloramfenikol bagi bayi baru lahir mnmbulkan sindrom bayi
kelabu. Krn bayi contains enzim glukuronil transferase dlm jml
rltf
sdkt, shg kemampuan mmtbls klramfenikol rdh, akibatya tjadi
penumpukan O pd jrgn & mnmbulkan efek yg tdk diinginkan
• Bayi br lhr contain enzim glukuronil sdkt. Pberian salisilat,
klrmfenikol, klorpromazin dpt mnmbulkan neonatal
hyperbilirubinemia (kern ichterus). Hal ini disebabkan tjadi
kompetisi pd proses konjugasi antara bilirubin, suatu seny
endogen hsl pmcahan hemoglobin, dgn O di atas, shg bilirubin yg

Usia
tdk tmtbls tkumpul pd jrngn & mnmbulkan efek yg tdk diinginkan

. Heksobarbital, bila diberikan pd tikus yg baru lahir

dgn dosis 10 mg/kg BB, tikus ttdur selama lbh 6 jam;
sdg p’berian dgn dosis sama pd tikus dws hnya
mnyebabkan ttdur < 5 menit

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Induksi enzim metabolisme Inhibisi Enzim Metabolisme
• Fenobarbital, dpr m’induksi enzim • Kdg-kdg pberian tlbh dahulu or sec
ikrosom shg mn’katkan mtblm warfarin & ¯ bsama-sama suatu seny yg dpt mghbt
efek antikoagulannya. Pasien yg diobati dgn kerja enzim mtbm dpt :
warfarin & akan diberi fenobarbital, dosis 1. Meningkatkan intensitas efek O
warfarin hrs disesuaikan (diperbesar) Induksi 2. mp’pjng masa kerja O
• Rokok contain polisiklik aromatik enzim 3. Meningkatkan kemungkinan efek
hidrokarbon, spt benzo(a)piren, yg dpt metaboli samping
m’induksi enzim mikrosom, yi sitokrom P- 4. efek toksisitas
450, shg oksidasi dr bbrp O spt teofilin, sme contoh :
fenasetin, pentazosin & propoksifen. Cth: • Dikumarol, kloramfenikol, sulfonamida
waktu paro teofilin pd perokok 4,1 jam; pd & fenilbutazon dpt mhbt enzim yg
tdk perokok 7,2 jam mmtbls tolbutamid & klorpopamid, shg
• Fenobarbital, dpt kecep mtblm respons glikemi
griseofulvin, kumarin, fenitoin, • Dikumarol, kloramfenikol & isoniazid
hidrokortison, testosteron, bilirubin, dpt mhbt enzim mtblm dr fenitoin,
asetaminofen & O kontrasepsi oral sulfonamida, sikloserin & para-amino
• Fenitoin, dpt kcptn mtblm kortisol, salisilat, shg kadar O dlm serum drh &
nortriptilin, & O kontrasepsi oral toksisitasnya pula.
• Fenilbutazon, dpt kcptn mtblm aminopirin • Fenilbutazon, sec stereoselektif dpt
& kortisol mhbt mtblm (s)-warfarin, shg aktivitas
Inhibisi antikoagulannya (hipoprotombonemi).
Induksi enzim jg mp’aruhi toksisitas bbrp O Bila luka tjdi prdrhn yg hebat
krn dpt mn’katkan mtblm & pbtkn mtblt Enzim
reaktif. Metabolis
Cth: induksi enzim sitokrom P-450 oleh me
fenobarbital akan oksidasi asetaminofen,
shg pbtkn mtblt reaktif imidokuinon &
hepatotoksisitasnya mjadi lbh bsr.
Faktor lain-lain
1. Diet makanan
2. Keadaan kekurangan gizi
3. Gangguan keseimbangan hormon
4. Kehamilan
5. Pengikatan Obat oleh protein plasma
6. Distribusi Obat dlm jaringan
7. Keadaan patologis hati, misal kanker hati.

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 Status gizi
 Diet protein rendah menurunkan reaksi oksidasi & konjugasi
= defisiensi AA sperti glisin
 Defisiensi vitamin E deficiency menurunkan dealkilasi & hidroksilasi
 Defisiensi Ca, Mg, Zn menurunkan kapasitas metabolisme
obat pada defisiensi Fe
 Defisiensi Essential fatty acid (esp. Linoleic acid) menurunkan
metabolisme ethyl morphine and hexobarbital
Strategies to manage drug
metabolism

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1)-Pharmaceutical strategies:
by using different dosage forms to either avoid or compensate for rapid
metabolism.
1- Sublingual tablets (through mucous mermbrane) by delivering drugs
directly to blood and bypassing first-pass effect as nitroglycerine
(antiangina drug).
2- Transdermal patches and ointments: provide continuous supply of drug
over extended period of time and are useful for rapidly metabolizing
drugs suchj as prophylactic nitroglycerine.
3- Intramuscular injections provide a continuous supply of drug over extended
period of time such as`lipid soluble esters of estradiol and testosterone.
Hydrolysis of these prodrugs produce a steady supply of rapidly
metabolized hormones.
4- Enteric coated formulation can protect acid-sensitive drugs as erythromycin.
5- Nasal administration allows for the delivery of peptides such as aerosols
since they need only to penetrate the thin epithelial layer to reach
the abundant capillary beds
2)-Pharmacological strategies
These involve the concurrent use of enzyme inhibitors to decrease drug
metabolism. Sometimes the concurrent use of an additional agent doesn’t
prevent metabolism but prevents the toxicity caused by metabolites of
the therapeutic agent.

1- Levodopa, the aminoacid precursor of dopamine, in the treatment

of Parkinson’s disease. Carbidopa , a dopa decarboxylase inhibitor

2- β-Lactam antibiotics activity is reduced by micoorganisms capable of

secretin β–lactamase enzymes. Clavulanic acid is a β–lactamase inhibitor
used in conjunction with penicillin antibiotics.
3)-Chemical strategies
These are molecular modifications involving the
addition, deletion or isosteric modification of
functional groups.
Examples are:
1-chlorpropamide was designed from
tolbutamide 2-Methyl testosterone was designed
from
testosterone.
41
 Prodrugs strategies
Prodrugs are used instead of active form of
the drug to:
a) Enhance membrane permeability,
b) Reduce drug toxicity
c) Overcome /mask bad taste
d) Overcome acid sensitivity
e) Prolong (short) duration.

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 Advantages of Prodrugs
1- An increase in water solubility by using sodium succinate esters as
chloramphenicol succinate IV injection.
2- An increase in lipid solubility
a-Increase duration of action by using lipid soluble esters
b-Increase oral absorption as by using esters of the highly polar drugs or N-
methylation
c-Increase topical absorption of steroids by masking OH group as esters or
acetonides.
3-A decrease in water solubility to increase palatability as in chloramphenicol
palmitate
4- Decrease GI irritation (side effect) as in aspirin

5- Site specificity as in methyl dopa

6- Increased half-life and chemical stability as in cefamandole acetate a stable
prodrug, while the parent cefamandole is unstable solid dosage form.
Hetacillin is another prodrug (for ampicillin ).