Farmakokinetika

Sri Wahyuni, S. Farm., Apt

Quiz

What is pharmacokinetics?

What your body does to the drug

The quantitative analysis of the time course of
drug

What are the steps of pharmacokinetics?

Absorption
Distribution
Metabolism
Excretion

Nasib Obat dalam Tubuh

(Farmakokinetika)
Apa yang
terjadi pada
obat setelah
masuk ke tubuh kita ?

Definition: quantitative study of

absorption, distribution, metabolism,
and elimination of chemicals in the
body, as well as the time course of
these effects.
Summary:
- absorption
- distribution
- metabolism
4
- elimination

Pharmacokinetics: science that studies routes of administration,

absorption* and
distribution*, bioavailability, biotransformation, and excretion of
drugs.

*key factors in the drug experience

Farmakokinetik

Bioavailabilitas

Rute pemberian
Absorpsi
Distribusi
- Difusi
- Kelarutan lipid
- Ionisasi
- Ikatan depot
Metabolisme
Ekskresi

Farmakodinamik

Aksi Obat

Reseptor
- Hubungan
dosis-respon
- Antagonisme

Efek Obat

-Efek samping
-Indeks terapi
-Perubahan perilaku

Concentration of a drug at its site of action is

a fundamental determinant of its
pharmacologic effects.
Drugs are transported to and from their sites
of action in the blood because of that: the
concentration at the active site is a
function of the concentration in the blood.
The change in drug concentration over time in
the blood, at the site of action, and in other
tissues is a result of complex interactions of
multiple biologic factors with the
physicochemical characteristics of the drug.

Pharmacokinetics

Drug molecules interact with target sites to effect

the nervous system

The drug must be absorbed into the bloodstream and

then carried to the target site(s)

Pharmacokinetics is the study of drug absorption,

distribution within body, and drug elimination

Absorption depends on the route of administration

Drug distribution depends on how soluble the drug
molecule is in fat (to pass through membranes) and on
the extent to which the drug binds to blood proteins
(albumin)
Drug elimination is accomplished by excretion into urine
and/or by inactivation by enzymes in the liver

ADME

Processes that Determine Drug PK

Absorption: how the drug enters the blood

The amount of acid in stomach or amount of food changes

the amount of drug absorbed

This is why some drugs must be taken with or without food or

can not be taken with antacids

Distribution: how the drug travels in the blood and

how it goes into and out of other areas of the body

Metabolism: how the body changes a drug usually

in intestine and liver

Drug Elimination: how the body gets the drug out:

via kidneys through urine or

via liver though stool

http://www.thebody.com/content/art875.html

Routes of Administration

Cara/jalur pemberian
(Routes of administration)
Bagaimana dan di mana obat memasuki tubuh akan
menentukan seberapa banyak obat mencapai
tempat aksinya dan, pada gilirannya, menentukan
besarnya efek
Jalur pemberian dapat mempengaruhi absorpsi obat
Yang menentukan adalah :
Luas permukaan absorpsi
Banyaknya membran/barrier yang harus dilewati
Banyaknya obat yang terdegradasi
Jumlah ikatan dengan depot

Macam cara pemberian obat:

Intravenous Injections (i.v.)

Intramuscular Injections (i.m.)
Subcutaneous Administration (s.c.)
Intraperitoneal Injections (i.p.)
Inhalation
Oral Administration (p.o.)
Other (e.g., Sublingual, Topical,
Transdermal, etc.)

Injeksi subcutaneous

Sublingual
Injeksi Intramuscular

Intra vena

Inhalasi

ip

Anestesi epidural, pada

akan melahirkan

Anestesi epidural, pada ibu yang

akan melahirkan

Sebelum dapat memberikan

efek, obat harus masuk ke
dalam sirkulasi sistemik

Routes of administration

Cp max
Tmax
Onset
Cl
T1/2

Time course of drug blood levels depends on route of

administration. They are also associated with differential duration
of drug effect

Overview

Liberation

Applies to drugs given orally

Components

Release of drug from pill, tablet, capsule

Dissolving of active drug in GI fluids

Ex:
Ex:Enteric
Entericcoated
coated
aspirin
aspirinslows
slowsabsorption
absorptionin
in
stomach
vs
non-coated
stomach vs non-coated

Absorption

Movement from administration site into

circulation

Absorpsi Obat

Adalah perpindahan obat dari tempat pemberian

menuju ke sirkulasi darah dan target aksinya
Untuk memasuki aliran sistemik/pembuluh darah
obat harus dapat melintasi membran/barrier
merupakan faktor terpenting bagi obat untuk
mencapai tempat aksinya ( misal: otak,
jantung,anggota badan lain)
Obat harus dapat melewati berbagai membran sel
(misalnya sel usus halus, pembuluh darah, sel glia
di otak, sel saraf)

Mekanisme perpindahan/
transport obat

Difusi pasif:
Perpindahan obat/senyawa dari kompartemen yang
berkonsentrasi tinggi ke konsentrasi rendah
merupakan mekanisme transport sebagian besar
obat
Transport aktif
Perpindahan obat/senyawa dari kompartemen yang
berkonsentrasi rendah ke konsentrasi tinggi
membutuhkan energi dan protein pembawa/carrier
mekanisme transport obat-obat tertentu

Difusi Pasif

Senyawa lipofilik
Senyawa hidrofilik

Transport Aktif

carrier

Difusi pasif:

Tergantung pada:
ukuran dan bentuk molekul obat
kelarutan obat dalam lemak
derajat ionisasi obat

Pengaruh kelarutan obat dalam lipid

Membran sel tersusun oleh molekul lipid (lemak)

Akibatnya, obat yang dapat larut dalam lipid (lipid soluble) akan
berdifusi melalui membran lebih mudah dibandingkan obat yang
larut dalam air (water soluble)

Kelarutan obat dalam lipid dinyatakan sebagai Koefisien Partisi (P)

angka yang menunjukkan perbandingan kelarutan obat dalam
lipid dan air

P = rasio obat yang tidak terionkan yang terdistribusi pada fase air
dan lipid pada keadaan kesetimbangan (equilibrium).
Po/w = (Coil/Cwater)equilibrium

P > 1 : lipofilik; P < 1 : hidrofilik

Dengan demikian, faktor utama kelarutan dalam lipid adalah derajat

ionisasi

Derajat ionisasi

Adalah banyaknya obat yang terionkan (menjadi

bermuatan)
ketika dilarutkan dalam air
Faktor penentu utama ionisasi:
Sifat asam-basa obat : asam lemah atau basa lemah
(sebagian besar obat adalah asam lemah atau basa lemah)

Sifat asam-basa cairan solven (pelarut)-nya : asam

atau
basa
(obat yang bersifat asam lemah akan lebih terionisasi pada
suasana basa, sedangkan obat yang bersifat basa lemah akan
terionisasi pada suasana asam)

Contoh obat dan sifat keasamannya

Asam

Basa

Levodopa

Diazepam

Klordiazepoksid

Penisilin

Aspirin

Trimetoprim

Makin asam

Morfin

Metotreksat

Norepinefrin

Sulfametoksazol

Dopamin

Klorotiazid

Propranolol

Fenobarbital

Amfetamin

Fenitoin

Klorokuin

Asam askorbat

Makin basa

Aturan:

Molekul akan menjadi kurang bermuatan (tidak terionisasi )

jika
berada pada suasana pH yang sama, dan akan lebih
bermuatan jika
berada di pH yang berbeda

Semakin bermuatan, suatu molekul akan semakin sulit

menembus membran

Semakin kurang bermuatan, suatu molekul akan lebih mudah

menembus membran

Dapat menjadi prediktor terhadap sifat absorpsi obat

Contoh:
Aspirin (bersifat asam lemah) akan lebih mudah terabsorpsi
di lambung atau usus ?
Mengapa ?

Factors Affecting Liberation/Absorption

Formulation factors

Tablet disintegration
Inert ingredient /
solvent effects
Solubility
Drug pH
Concentration

Patient factors

Absorbing surface
Blood flow
Environmental pH
Disease states
Interactions with food,
other drugs

Membranes and Absorption

Lipid Bilayer

Small,
uncharged

H2O, urea,
CO2, O2, N2

Swoosh!

Large,
uncharged

Glucose
Sucrose

DENIED!

Small
charged
ions

H+, Na+,
K+, Ca2+,
Cl-, HCO3-

DENIED!

A real live, actual clinical question...

Aspirin
Aspirinisisan
anacidic
acidicdrug.
drug.In
Inthe
thestomach
stomachwill
willititexist
existmostly
mostly
in
inionized
ionizedor
ornon-ionized
non-ionizedform?
form?

NON-IONIZED
Why?
Why?

How will this affect aspirin

absorption?
Lipid Bilayer

Ionized
Ionized form
form
(charged)
(charged)

A-

Ionized
Ionized form
form
(uncharged)
(uncharged)

HA

HA

Moral of the story...

Acidic drugs are best absorbed from

acidic environments

Basic
Basicdrugs
drugsare
arebest
bestabsorbed
absorbedfrom
from
basic
basicenvironments
environments

So...

To
Toabsorption
absorptionof
ofan
anacidic
acidicdrug
drug
acidify
acidifythe
theenvironment
environment

To
Toabsorption
absorptionof
ofan
anacidic
acidicdrug
drug
alkalanize
alkalanizethe
theenvironment...
environment...

Absorpsi pada Blood-Brain Barrier

(sawar darah otak)
Khusus untuk obat-obat yang tempat aksinya ada di otak, ia harus
dapat menembus sawar darah otak
Guna sawar darah otak : melindungi otak dari bahan-bahan yang
mungkin berbahaya

Agar dapat menembus sawar darah otak,

suatu obat harus :

Tetap tidak terionkan pada pH darah

Memiliki koefisien partisi yang tinggi (larut dalam lipid)

Atau, menggunakan bantuan suatu

mekanisme transport (misalnya: L-DOPA)

Contoh :

Distribution

Rate of perfusion
Plasma protein (albumin) binding
Accumulation in tissues
Ability to cross membranes

Blood-brain barrier
Placental barrier

Distribution

The movement of drug from the blood

to and from the tissues

Distribusi -- Ikatan depot

Adalah ikatan suatu obat dengan suatu bagian tidak
aktif, seperti albumin (pada darah), otot, tulang,
lemak, atau liver.
Perlu diingat bahwa:
Efek suatu obat tergantung kepada konsentrasi obat
di tempat
aksinya (reseptor)
Hanya obat dalam bentuk bebas (tidak terikat) yang
dapat dengan bekerja di tempat aksinya
menghasilkan efek
Obat terikat dan tidak
terikat berada dalam
D + A DA
kesetimbangan dalam darah, digambarkan dgn
persamaan sbb:

Efek ikatan depot terhadap efek terapi

Plasma Protein Binding

Many drugs bind to plasma proteins in the blood

steam
Plasma protein binding limits distribution.
A drug that binds plasma protein diffuses less
efficiently, than a drug that doesnt.

Plasma Protein Binding

warfarin
warfarin(Coumadin)
(Coumadin)isishighly
highlyprotein
proteinbound
bound(99%).
(99%).Aspirin
Aspirin
binds
bindsto
tothe
thesame
samesite
siteon
onserum
serumproteins
proteinsas
asdoes
doesCoumadin.
Coumadin.
IfIfaapatient
patienton
onCoumadin
Coumadinalso
alsotakes
takesaspirin,
aspirin,what
whatwill
willhappen?
happen?

The available Coumadin

will increase.
1)
1)Why?
Why?
2)
2)Why
Whydo
dowe
wecare?
care?

Blood-Brain Barrier
The
The blood
blood brain
brain barrier
barrier consists
consists of
of cell
cell tightly
tightly
packed
packed around
around the
the capillaries
capillaries of
of the
the CNS.
CNS.
What
What characteristics
characteristics must
must aa drug
drug possess
possess to
to
easily
easily cross
cross this
this barrier?
barrier?

Non-protein bound, non-ionized, and highly lipid soluble

Why?
Why?

Elimination

The irreversible removal of the parent drugs

from the body
Elimination

Excretion

Drug Metabolism
(Biotransformation)

Metabolism (Biotransformation)

Two effects

Transformation to less active metabolite

Enhancement of solubility

Liver = primary site

Liver disease

Slows metabolism
Prolongs effects

Metabolisme
(biotransformasi)

Suatu proses kimia di mana suatu obat diubah

di dalam tubuh
menjadi
suatumetabolitnya
Organ metabolisme utama : liver/hepar

Hasil metabolisme bisa :

Lebih atau kurang aktif, inaktif, atau tidak berubah,
dalam kaitannya dengan aktivitasnya
umumnya
menjadi bentuk yang kurang aktif

Hepatic First-Pass Metabolism

Affects orally administered drugs

Metabolism of drug by liver before drug
reaches systemic circulation
Drug absorbed into portal circulation, must
pass through liver to reach systemic
circulation
May reduce availability of drug

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 mengalamifirst past metabolism akan

kurang bioavailabilitasnya

efek berkurang

Intravenous
Administration
Oral
Administration

Metabolis
m

Liver

Intestines

Type Metabolisme
Nonsynthetic Reactions (Reaksi Fase I)
Oxidasi, reduksi, hydrolysis, alkilasi, dealkilasi
Metabolitnya bisa lebih aktif/tidak dari pada senyawa
asalnya
Umumnya tidak dieliminasi dari tubuh kecuali dengan
adanya
metabolisme lebih lanjut
Synthetic Reactions (Reaksi Fase II)
Konjugasi (glukoronidasi, sulfatasi)
Penggabungan suatu obat dengan suatu molekul lain
Metabolitnya pada umumnya lebih larut dalam air dan
mudah diekskresikan

Skema metabolisme obat

Absorpsi

Metabolisme
Fase I

Obat A

Obat B

Eliminasi
Fase II
Konjugasi

aktif

Konjugasi

inakti
f

Konjugasi

Obat C
Obat D

aktif
inaktif

Lipofilik

Hidrofilik

Faktor yang mempengaruhi metabolisme

obat
1. Induksi enzim: dapat meningkatkan kecepatan biotransmormasi
dirinya sendiri, atau obat lain yang dimetabolisme oleh enzim yang
sama

dapat menyebabkan toleransi

2. Inhibisi enzim: kebalikan dari induksi enzim, biotransformasi obat

diperlambat

bioavailabilitas meningkat

efek menjadi lebih

besar dan lebih lama

3. Kompetisi (interaksi obat) : terjadi pada obat yang dimetabolisir
oleh sistem enzim yang sama (contoh : alcohol dan barbiturates)
4. Perbedaan individu: karena adanya genetic polymorphisms,
seseorang mungkin memiliki kecepatan metabolisme berbeda
untuk obat yang sama

Consequences Of Metabolism

Drug metabolism != Drug inactivation

The metabolite may have

Equal activity to the drug

No or reduced activity
Increased activity (Prodrugs)
Toxic properties, not seen with the parent drug

Elimination

Kidneys = primary site

Mechanisms dependent upon:

Passive glomerular filtration

Active tubular transport

Partial reabsorption
Hemodialysis

Renal disease

Slows excretion
Prolongs effects

Eliminasi/ekskresi

Obat akan dieliminasi dari dalam tubuh dalam bentuk

metabolitnya
atau bentuk tidak berubah

Organ ekskresi utama adalah ginjal

urin

Namun bisa juga melalui : paru-paru, keringat, air liur,

feses, ASI

T1/2 (half-life) : waktu yang

dibutuhkan obat sehingga
konsentrasinya dalam
darah menjadi separonya

Active Tubular Transport

Probenecid
Probenecid is
is moved
moved into
into the
the urine
urine by
by
the
the same
same transport
transport pump
pump that
that moves
moves
many
many antibiotics.
antibiotics. Why
Why is
is probenecid
probenecid
sometimes
sometimes given
given as
as an
an adjunct
adjunct to
to
antibiotic
antibiotic therapy?
therapy?
It competes with the antibiotic at the pump and slows
its excretion.

Urine pH and Elimination

AA patient
patient has
has overdosed
overdosed on
on phenobartital.
phenobartital.
Phenobarbital
Phenobarbital is
is an
an acid.
acid. IfIf we
we alkalinalize
alkalinalize the
the
urine
urine by
by giving
giving bicarbonate
bicarbonate what
what will
will happen
happen
to
to the
the phenobarbital
phenobarbital molecules
molecules as
as they
they are
are
filtered
filtered through
through the
the renal
renal tubules?
tubules?

They will ionize...

How will this affect phenobarbital

reabsorption by the kidney?
Non-ionized
HA

Ionized
H+ + A-

Decreased
Decreasedreabsorption
reabsorption

Increased
Increasedelimination
elimination

Thank U.... Matur Nuwun...

See U... Next

week

ADME - Summary

Plasma Concentration

PK Definitions
Cmax: Maximum
concentration may relate to
some side effects

10000

AUC: Area under the curve

(filled area) = overall drug
exposure

3000

1000

Cmin: minimum or
trough
concentrations: may
relate with efficacy of
HIV drugs

100
0

10

Time Postdose (hr)

http://www.thebody.com/content/art875.html

12

Drug Levels & Resistance

How Do Drug Interactions Happen?

They occur due to changes in the
pharmacokinetics
of a drug
Changes in the absorption, distribution,
metabolism and excretion (ADME) of a drug
Toxic

Concentration

Effective

Ineffective
0
24

TIME

12

18

Concentration versus Time Profiles

Broadly the concentration time profiles can be viewed as two diffe

One-Compartment Model

Dose

Assumes body as one compartment

1
k

Two-Compartment Model
Central compartment (drug entry and
elimination)

Dos
e

Tissue compartment (drug distributes)

The one compartment model

linear assumes that the
drug in question is evenly
distributed throughout the
body into a single
compartment.
This model is only appropriate
for drugs which rapidly and
readily distribute between
the plasma and other body
tissues.

The distribution phase for aminoglycosides is

only 15-30 minutes, therefore, we can use a
one-compartment model with a high degree
of accuracy

Drugs which exhibit a slow

equilibration with
peripheral tissues, are
best described with a
two compartment model

Vancomycin is the classic example, it's distribution

phase is 1 to 2 hours. Therefore, the serum level time
curve of vancomycin may be more accurately
represented by a 2-compartment model.

Plasma Concentration-Time Profile for a Drug Following a

Single Oral Dose

Rate of drug accumulation

at any time:
dDBODY/dt= dDABS/dt dDELIM/dt
Absorption Phase:
dDABS/dt > dDELIM/dt
At time of peak drug conc.:
dDABS/dt = dDELIM/dt
Post-absorption Phase:
dDABS/dt < dDELIM/dt

Effect of a Change in Absorption Rate Constant (Ka) on Plasma

Drug Concentration Versus Time Curve

0.5/hr

0.2/hr

Open one-compartment model

process of distribution to each compartment is

much faster than absorption into blood and
elimination
drug concentration everywhere in the
compartment is equal (CSTR)
elimination processes are pseudo-1st order
Vd

ka
D

Cp

DB

kel

CHEE 440

B. Amsden