FARMAKOKINETIK

(ABSORBSI & METABOLISME)

Hijra Novia Suardi

Depart. Farmakologi dan Terapeutik

FK Unsyiah

PHARMACOLOGY
Pharmacokinetics
What the body does to the drugs

Absorption
Distribution
Biotransformation
Excretion

Pharmacodynamic
What the drug does to the body
Pengobatan rasional

Schematic representation of the interrelationship of the

absorption, distribution, binding, biotransformation, and excretion
of a drug and its concentration at its locus of action.

Clinical Pharmacokinetics (3)

4 most important pharmacokinetics
parameters that dictate adjustment of dosage
in individual patients:
clearance (a measure of the bodys ability to eliminate
drugs);
volume distribution (a measure of the apparent space
in the body available to contain the drug);
elimination half-life ( a measure of rate of removal of
drug from the body);
It is the time it takes for the plasma concentration as the
amount of drug in the body to be reduced by 50%.
and bioavailability (the fraction of drug absorbed as
such into the systemic circulation).

ABSORPTION
Movement of drug from the site of administration into the
blood stream
Administration of drug:
ORAL (ENTERAL) the most important
Sublingual

PARENTERAL
= Intravenous (IV)
= Subcutaneus (SC)

= Intra muscular (IM)

= Intra cutaneous (IC)

= Intra peritoneal (IP)

= intra articular

Suppository (rectal, vaginal)

Administration by IV : no absorption

Oral route of administration

Most important route of administration
Major site of absorption : small intestine
with surface area of abs. : + 200 m2
Other site of absorption: stomach (gaster)
Rate of absorption is influenced by:
Surface area
- Blood flow
pH (degree of ionization)
- Molecular weight
Solubility of drug
Bowel movement

ABSORPTION
How does absorption occur ?
1.

Passive diffusion:
Absorption method for most drugs
Energy independent
Following concentration gradient
2. Active transport
Energy dependent
May opposite concentration gradient
3. Facilitated diffusion
Memerlukan transporter

ABSORPTION
Ada 2 jenis transporter utk obat
Transporter utk efflux atau eksport obat ABC (ATPBinding Cassette) Transporter
P-Glikoprotein (P-gp)
Multidrug Resistance Proteins (MRP)
Perlu energi
Transporter untuk uptake obat
Organic anion transporting polypeptide (OATP)
Organic anion transporter (OAT)
Organic kation transporter (OCT)
energi

1. Difusi Pasif
Rate of diffusion is proportional to :
degree of ionization (depends on the pH of
drug and environment)
lipid solubility of the drug molecule
concentration gradient across the membrane
(the driving force)
Surface area of absorption

1. Difusi Pasif

Tidak membutuhkan energi

Molekul obat melarutkan diri dlm lemak
membran sel
Obat bergerak dari sisi yg kadarnya lebih tinggi
ke sisi lain sampai tercapai steady state (taraf
mantap) --> kadar obat non-ion di kedua sisi
membran sama

Obat asam lemah:

pd suasana asam non-ion >>> absorpsi
lebih baik
Obat basa lemah :
pada suasana basa non-ion >>> absorpsi
lebih baik

2. Transport aktif
Perlu energi --> dpt melawan perbedaan kadar/
potensial listrik
Terutama di usus halus
Untuk zat2 mknan: glukosa, asam amino, bbrp
vitamin
Obat2 yg struk. kimia mirip struk. zat makanan:
levodopa, metildopa
Memakai carier

Physicochemical factors in transfer of drugs

across membrane
Drug factors:
Size, shape, degree of ionization, lipid solubility,
protein binding

Membrane factors:
A bilayer amphiphatic lipids
Protein serve as receptors, channels, or transporter

Type of transport
passive diffusion, active transport, facilitated diffusion

Faktor2 yg Mempengaruhi Absorbsi Obat

dlm Sal. Cerna
1.
2.
3.
4.

Formulasi & karakteristik obat

Karakteristik pasien
Keberadaan substrat lain dlm sal. cerna
Sifat farmakokinetik obat

Faktor2 yg mempengaruhi absorbsi

obat dlm sal cerna
1. Formulasi &
karakteristik obat
a)
b)
c)
d)

Waktu disintegrasi
Waktu disolusi
Eksipien
Stabilitas dlm sal.cerna

2. Karakteristik pasien
a) pH sal. Cerna
b) Kecepatan
pengosongan lambung
c) Waktu transit dlm usus
d) Luas permukaan
absorbsi
e) Penyakit sal. cerna
f) Aliran darah usus

Faktor2 yg mempengaruhi
absorbsi obat dlm sal cerna
3. Keberadaan substrat
lain dlm sal. Cerna

4. Sifat farmakokinetik
obat

a) Interaksi dg obat2
lain
b) makanan

a) Metab. obat dlm

lumen sal. cerna
b) Metab. obat oleh
flora usus

Alternative sites of drug

absorption
1. Intramuskular

Dirusak di lambung (mis. Benzilpenisilin)

Dimetab. sec ekstensif & eliminasi presistemik (mis.
Lidokain)
Obat lgs masuk interstitium jaringan otot atau kulit
pembuluh darah kapiler pembuluh darah sistemik
onset of action lebih cepat

Kecepatan & kelengkapan absorbsi (IM)

a. Kelarutan obat dlm air
Obat yg sukar lar. dlm air pd pH fisiologis mis. Digoksin,
fenitoin, diazepam --> mengendap di tmp suntikan --->
absorbsi lambat, tidak lengkap & tidak teratur.
b. Aliran darah di tempat suntikan
c. Otot yg disuntik ( m. deltoid)

2.Rektal

mual & muntah, tidak sadar, pascabedah

First pass metabolism relatif <
Sering mengiritasi mucosa rectum
absorbsi sering tdk lengkap & tdk teratur.
Obat ttt absorbsi hampir sama
(mis. diazepam supp.)

3. Paru-paru
Bentuk gas/ cairan yg mudah menguap
mis. anesthesi umum, btk aerosol
mis.isoprenalin
Absorbsi mel. mucosa sal nafas & epitel paru
Keuntungannya:
- absorbsi cepat --> permukaan absorbsi luas
- terhindar dari eliminasi presistemik
- obat dapat langsung di beri pada bronkus

4. Absorbsi Lokal mel. Mulut & Hidung

Bukal & sublingual:
- Kerja cepat
- terhindar dr met lintas pertama
- Kadar tinggi dalam darah
Kekurangan:
- Rasa
- Harus diletakan pd tmp ttt pada jangka waktu ttt, tidak
boleh ditelan/ dikunyah

Intranasal
Per oral --> degradasi ekstensif
Absorbsi jelek

Mata
Efek lokal pada mata
Efek sistemik krn absorbsi melalui kanal nasolakrimalis

Kulit
Keuntungan:
- Terhindar dari metabolisme presistemik
- Menghindari peaks and thoughs in plasma
concentration versus time curve
- Mengurangi variabilitas individu

Bioavailability
Definition: the amount of administered
drug which reaches systemic circulation in
active form
Depends on:
pharmaceutical factors
GI absorption
Presystemic metabolism (first pass metab.)

Bioavailability
Ingested
(100%)
100-A-B

( 100-A-B-C)%
Bioavailability (F)
B % metab.
In intest. wall
A%
Not absorbed
C% metab.
in liver

Absorption: (100-a)%

(b + c) % = presystemic
elimination/metabolism =
first-pass metabolism

FIRST PASS METABOLISM / ELIMINATION

Metabolism of drug before reaching systemic circulation
In intestinal mucosa and liver
Reduces the bioavailability of drug
In case of prodrug, FPM converts inactive drug to its
active form
FPM can be avoided or minimized by:
Sublingual administration
Rectal administration
Parenteral administration (IV, IM)

Metabolism = Biotrasformation
Main site of drug metabolism : the liver
Other tissues : intestine, kidneys, lung, blood, brain, skin
Aim of metabolism: to convert lipid soluble drugs to water
soluble (more polar) compounds can be excreted via
kidneys or bile
PHASE I: oxidation, reduction, hydrolysis
- drugs become inactive, less / more active, or toxic
- drugs obtain polar groups (-OH, -NH2, -COOH, SH) can
react with endogenous substrates in phase II reactions

Metabolism = Biotrasformation
PHASE II : conjugation
Conjugation with endogenous substrates
(glucuronic acid, sulphate, acetyl, glutathion)
- drugs almost always become inactive
Drug metabolism: Phase I reaction only, phase II
only, or phase I followed by phase II

Metabolic reactions (1)

Most important : oxidation by cytochrome P450 (CYP) in
liver microsomes
There are + 50 isoenzymes of CYP
Major CYPs for drug metabolism :
CYP3A4/5
metabolise > 50% drugs for human the most
important metabolic enz.
also expressed in intestinal epith. and kidney
CYP2D6 - the first known = debrisoquine hydroxylase
CYP2C9, CYP2C19
CYP1A2 - previously known as cytochrome P448
CYP2E1

Interactions in drug metabolism (1)

Induction of metabolic enzymes :
- rate of metabolism of drug substrates
pharmacokinetic tolerance
- requires 3 days to 1 wk before max. effect is
achieved
Inhibition of metab. enzymes : occur directly
directly conc. of drug substrates toxicity
Inhibition of metabolic enz. : - reversible
- irrevers., eg. grapefruit

Example :
Terfenadine, astemizole, cisapride (substrates of CYP3A4)
contraindicated with
ketoconazole, itraconazole, erythromycin, clarithromycin
(potent inhibitors of CYP3A4)

conc. of terfenadine, astemizole, cisapride

QTc interval (on ECG)

ventricular arrhythmias (torsades de pointes) death

Terfenadine : withdrawn in UK & USA (1998)
Astemizole : withdrawn worldwide (June 1999)
Cisapride : withdrawn worldwide (July 2000)

Metab. enzymes in liver cytosol

Sulfotransferase (ST)
N-acetyltransferase (NAT) : NAT1, NAT2
Glutathion S-transferase (GST)
Thiopurine methyltransferase (TPMT)
In general : conjugates more water soluble

GENETIC POLIMORPHISM
A number of genetic polymorphisms: poor, intermediate,
extensive, or ultrarapid metabolizer
CYP2D6
extensive vs poor metabolizers
CYP2C9
(EM vs PM)
CYP2C19
NAT2 : rapid vs slow acetylators (RA vs SA)
In South-east Asians :
- frequency of PM CYP2D6 : 1 - 2 %
- frequency of PM CYP2C19 : 15 - 25 %
- frequency of SA NAT2
: 5 - 10 %

Metabolisme
Aktivitas enzim dalam metabolisme obat yang
telah diteliti dan ternyata dipengaruhi oleh
adanya perbedaan ras/etnis, antara lain:
N-Asetil Transferase (NAT2)
individu diklasifikasi sebagai slow & rapid
asetilator
Sitokrom P450 subenzym CYP2C (CYP2C19 &
CYP2C9) dan CYP2D6
individu diklasifikasi sebagai poor & ekstensive
metabolizer

POLIMORFISME CYP2D6
Haloperidol me pd ras Cina
me pd ras Kaukasius

POLIMORFISME NAT
INH 60% bangsa eskimo rapid asetilator
60% bangsa eropa slow asetilator

Pharmacokinetic Interactions
ABSORPTION
Antacids are chelated by tetracycline and quinolones,
and the complex is not absorbed.
Cholestyramine adsorbs and inhibits the absorption of
thyroxine, cardiac glycosides, warfarin,
corticosteroids, and probably other drugs.
Anticholinergics slower gastric motility and increase
absorption of other drugs
Vit. C increase the absorption of Fe

 ABSORPTION
Antibiotics that alter the gastrointestinal flora
can reduce the rate of bacterial synthesis of
vitamin K enhances the effect of oral
anticoagulants
Digoxin is metabolised by GI microorganisms,
antibiotic therapy may result in an increase of
digoxin concentration

Transporter Interaction
Quinidine, verapamil : substrates & inhibitors of
P-gp
Digoxin : substrate of P-gp
interaction : plasma digoxin concentration
(inhibition of P-gp in the intestine & kidney)

 DISTRIBUTION
Many drugs are extensively bound to plasma albumin
(acidic drugs) or a1-acid glycoprotein (basic drugs).
Displacement of one drug from its binding site by
another might be expected to result in a change in drug
effects.
Warfarin + NSAID risk of bleeding
Oral anti diabetics + NSAID risk of hypoglycemia
Bilirubin + salicylate kern icterus in neonates

 METABOLISM
Phenobarbital, rifampicin, phenytoin: induces
cyt P-450
increases metabolism of other drugs
warfarin, quinidine, corticosteroids, estrogen
contraceptives, theophylline, mexiletine, and some
b-blockers.

Erithromycin, cimetidin: inhibits cyt P-450

inhibits metabolism of other drugs

Alcohol, phenobarbital: autoinduction

drug tolerance

 ELIMINATION
Probenecid inhibits biliary elimination of rifampicin
and indomethacin
Probenecid inhibits renal secretion of penicillin
prolongs the effects of penicillin
Pyrazinamid, thiazide: reduces renal excretion of uric
acid exacerbation of gout
Bicarbonate enhances water solubility of salicylate
reduces tubular reabsorption and increases excretion

Tabel 1. Berbagai faktor yang mempengaruhi absorbsi

obat melalui saluran cerna*
INTRALUMINAL
Sifat obat: berat molekul. Kelarutan dalam lipid, pKa, bentuk obat
(tablet, sirop)
Keadaan lumen saluran cerna
bakteri saluran cerna
interaksi dengan obat lain
bahan tambahan dalam obat (eksipiens, ajuvan)
bahan makanan
pH dalam saluran cerna
DINDING SALURAN CERNA
permukaan/mukosa saluran cerna
motilitas, aktivitas sekresi
pH epitel intestin
penyakit saluran cerna
aktivitas enzim (hidrolase, glukuronidase)
* Dimodifikasi dari Radde19