BAHAN AJAR UNTUK TOPIK MINGGU KE-4

Topic 4 : Kinetika Ikatan Obat - Protein

MATA KULIAH :

FARMAKOKINETIKA

Disusun oleh PJMK :

M.M. Farida Lanawati Darsono, S.Si.,M.Sc

Semester Genap
Tahun Akademik : 2021-2022

Universitas Katolik Widya Mandala Surabaya

Fakultas Farmasi

BU FARIDA_UKWMS 1
 Topic 4 : Kinetika - Drug Protein Binding
Kinetics of protein drug binding
 Hukum : Aksi Massa
 Reaksi :

 The kinetics of reversible drug–protein binding for a protein with one simple binding site
can be described by the law of mass action, as follows:

(persamaan 1)

The law of mass action, an association constant, K a, can be expressed as the ratio of the molar
concentration of the products and the molar concentration of the reactants.
This equation assumes only one-binding site per protein molecule

(persamaan 2)

Experimentally, both the free drug [D] and the protein-bound drug [PD], as well as the total
protein concentration [P] + [PD], may be determined. To study the binding behavior of drugs, a
determinable ratio (r )is defined, as follows

r=tetapan yg menunjukkan perilaku ikatan OP

moles of drug bound is [PD] and the total moles of protein is [P] + [PD], this equation becomes

(persamaan 3)

Substituting the value of PD from equa. 2

(persamaan 4)

BU FARIDA_UKWMS 2
This equation describes the simplest situation, in which 1 mole of drug binds to 1 mole of protein
in a 1:1 complex. This case assumes only one independent binding site for each molecule of drug.
If there are n identical independent binding sites per protein molecule, then the following is used:

(persamaan 5)
In terms of K d, which is 1/K a, Equation 6 reduces to

(persamaan 6)
Protein molecules are quite large compared to drug molecules and may contain more than one
type of binding site for the drug. If there is more than one type of binding site and the drug
binds independently on each binding site with its own association constant, then Equation 6
expands to

(persamaan 7)

The values for the association constants and the number of binding sites are obtained by various
graphic methods.

Penetapan tetapan ikatan dan tempat ikatan dg metode grafik

 Metode in vivo
 Metode in vitro

1. Direct plot
It is made by plotting r vresus (D)
Equation:

[D] vs r
Advantages: using direct data
Disadvantages: difficult to reach a saturated condition

BU FARIDA_UKWMS 3
2. graphic method = double reciprocal plot= klotz plot

Advantages: data bias 1/[D] vs 1/r

Disadvantages: non-linier

3. scatchard plot

Equation : (see ppt)

r/[D] = nka - rka

r vs r/[D]

Advantages: can be used for multiple binding sites – non linier

Disadvantages: variability >

4. rosenthall method

Equation : [DP]/[D] = nka[P] total – ka[DP]

Advantages: can be used for multiple binding sites – non linier

Disadvantages: variability >

5. Langmuir method

[D] vs [D]/r

Perbedaan antara obat bebas dengan obat terikat protein

Obat terikat protein plasma :
• Suatu komplek yang besar
• Tidak dapat lewat membran sel
• Distribusi terbatas
• Tidak aktif secara terapeutik
Obat bebas :
• Dapat lewat membran sel secara bebas
• Distribusi luas

BU FARIDA_UKWMS 4
• Aktif secara terapeutik

EFEK YANG DIINGINKAN DALAM PENGGUNAAN OBAT

• Hilangkan penyebab penyakit
• Hilangkan gejala penyakit
• Terapi untuk gantikan /menambah zat yang hilang/kurang

EFEK OBAT YANG TIDAK DIINGINKAN :

• Efek samping
• Efektoksik
• Alergi
• Teratogenik

EFEK SAMPING OBAT

• Pengertian : efek ikutan yang muncul setelah pemberian obat dengan dosis sesuai anjuran
• Efek samping : tidak dikehendaki, merugikan, membahayakan pasien
• Efek samping bersifat konsisten dan sudah diketahui

Significant of protein binding of drug

 Absorption –the binding of absorbed drug to plasma proteins decrease free drug conc. And
disturb equilibrium . Thus sink condition and conc. Gradient are established which now act
as the driving force for further absorption
 Systemic solubility of drug water insoluble drugs , neutral endogenous macromolecules ,
like heparin , steroids , and oil soluble vitamin are circulated and distributed to tissue by
binding especially to lipoprotein act as a barrier for such drug hydrophobic compound .
 Distribution -The plasma protein-drug binding thus favors uniform distribution of drug
throughout the body by its buffer function . A protein bound drug in particular does not cross
the BBB, placental barrier and the glomerulus

Tissue binding , apperent volume of distribution and drug storage

 A drug that bind to blood component remains confined to blood have small volume of
distribution.
 Drug that show extra-vascular tissue binding have large volume of distribution .
 the relationship b/w tissue drug binding and apparent volume of distribution

Vd = amount of drug in the body = X

plasma drug concentration C

the amount of drug in the body X = Vd . C

SIMILAR , amount of drug in plasma = Vp . S
Amount of drug in extravascular tissue = Vt .Ct

The total amount of drug in the body

Vd . C = Vp.C+Vt. Ct

where , Vp is volume of plasma

Vt is volume of extravascular tissue
Ct is tissue drug concentration

Vd = Vp + Vt Ct/C ………………….(1)

BU FARIDA_UKWMS 5
Dividing both side by C in above equation
The fraction of unbound drug in plasma (fu)

fu = conc. of unbound drug in plasma = Cu

total plasma drug concentration C

The fraction unbound drug in tissue (fut)

fut = Cut
Ct

Assuming that equilibrium unbound or free drug conc. In plasma and tissue is equal
C t = fu
C fut

mean Cu = Cut then ,

Vd = Vp + Vt . fu
fut

substituting the above value in eqution above

It is clear that greater the unbound or free concentration of drug in plasma larger its Vd

What is the effect of protein binding on drug action?

 For a drug showing little protein binding, the plasma acts simply as a watery solution in
which the drug is dissolved.
 Where protein binding does occur the behaviour of the drug may be influenced in several
ways:
1. Extensive plasma protein binding will increase the amount of drug that has to be absorbed
before effective therapeutic levels of unbound drug are reached. For example, acidic dugs
(such as acetyl salicylic acid – aspirin) are often substantially bound to albumin.
2. Elimination of a highly bound drug may be delayed. Since the concentration of free drug is
low, drug elimination by metabolism and excretion may be delayed. This effect is
responsible for prolonging the effect of the drug digoxin
 Changes in the concentration of plasma proteins will influence the effect of a highly bound
drug.
 A low plasma protein level may occur in old age or malnutrition. It may also be caused by
illness such as liver disease (remember that most plasma proteins are made in the liver), or
chronic renal failure where there is excessive excretion of albumin. In each case the result is
a smaller proportion of drug in bound form and more free drug in the plasma.
 The greater amount of free drug is able to produce a greater therapeutic effect and reduced
drug dosages may be indicated in these cases.
 Drugs may compete for binding with plasma proteins leading to interactions.
 This is significant for highly bound drugs such as the anticoagulant warfarin since even a
small change in binding will greatly affect the amount of free drug.
 Such an effect is produced by the concurrent administration of aspirin, which displaces
warfarin and increases the amount of free anticoagulant

BU FARIDA_UKWMS 6
PUSTAKA : SHARGEL- BIOFARMASETIKA – FARMAKOKINETIKA

LATIHAN 1:

BU FARIDA_UKWMS 7
BU FARIDA_UKWMS 8
BU FARIDA_UKWMS 9