Bahan Ajar Farmakokinetika-Bu Farida PDF

BAHAN AJAR
MATA KULIAH FARMAKOKINETIKA
Penyusun/Pengampu:
M.M. Farida Lanawati Darsono, S.Si., M.Sc.
Universitas Katolik Widya Mandala

FAKULTAS FARMASI
Surabaya
1
Fakultas Farmasi
Unika Widya Mandala Surabaya
Tatatp
Muka
Ke
Rencana Program dan Kegiatan Pembelajaran Semester (RPKPS)

(Q-004)
Nama Mata Kuliah
: Farmakokinetika
Kode Mata Kuliah
: PHR 470 (MKB)
Pilihan/Wajib*)
Semester
: 7
Prasyarat : Biofarmasetika
Jumlah SKS
: 1 sks
Kosyarat : Program Studi
: S 1 Farmasi
Tahun Akademik
: 2014/2015/Semester Gasal
Pokok Bahasan
1
I
II
Dosen
Pustaka
4
Farida L.D.,M.Sc
5
Shargel & Yu (1999)
3
Introduction to pharmacokinetics &
Pharmacokinetics versus route of
delivery
Distribution (I)
Farida L.D.,M.Sc
Shargel & Yu (1999)
III
Distribution (II)
Farida L.D.,M.Sc
Rowland & Tozer (1989)
IV
Drug protein binding
Farida L.D.,M.Sc
Kinetics of drug protein binding
Farida L.D.,M.Sc
Gibaldi (1984)
VI
VII
Non Linear pharmacokinetics

Michaelis Menten Equation
Farida L.D.,M.Sc
Farida L.D.,M.Sc
Gibaldi (1984)
VIII
UTS
IX
Hepatic and biliary metabolism (I)
Drs. Kuncoro Foe, Ph.D
Hepatic and biliary metabolism (II)
Shargel & Yu (1999)
XI
Hepatic and biliary metabolism (III)
Shargel & Yu (1999)
XII
Renal excretion (I)
Shargel & Yu (1999)
XIII
XIV
XV
Renal excretion (II)

Renal excretion (III)
Introduction to multiple dosage regimen

Ritschel (1984)
Ritschel (1984)
Shargel & Yu (1999)
XVI
UAS
References:
1. Gibaldi, M., 1984. Biopharmaceutics and Clinical Pharmacokinetics. Lea and Febiger, Philadelphia.
2. Ritschel, W.A., 1984. Graphic Approach to Clinical Pharmacokinetics. JP Prous Publishers.
3. Rowland, M. and Tozer, T.N., 1989. Clinical Pharmacokinetics. Lea and Febiger, Philadelphia.
4. Shargel, L. and Yu, A.B.C., 1999. Applied Biopharmaceutics and Pharmacokinetics. McGraw-Hill, Inc., New
York.
PJMK,
ttd
Drs.Kuncoro Foe,Ph.D.,Apt
2
Sistem penilaian
Dosen 1 : MM Farida Lanawati Darsono, S.Si.,M.Sc

tatap muka : 7 kali (sebelum UTS)*
Dosen 2 : Drs. Kuncoro Foe, G.Dip.Sc.,Ph.D.,Apt
tatap muka : 7 kali (sesudah UTS)
Nilai UTS dan UAS @ : 100

Nilai akhir : {(40 x UTS) + {60 x UAS)}/100
* Nilai UTS : 80 nilai ujian + 20 nilai tugas
References (for all topic)
Gibaldi, M., 1984. Biopharmaceutics and Clinical Pharmacokinetics. Lea and Febiger,
Philadelphia.
Ritschel, W.A., 1984. Graphic Approach to Clinical Pharmacokinetics. JP Prous Publishers.
Rowland, M. and Tozer, T.N., 1989. Clinical Pharmacokinetics. Lea and Febiger, Philadelphia.
Shargel, L. and Yu, A.B.C., 1999. Applied Biopharmaceutics and Pharmacokinetics. McGrawHill, Inc., New York
Shargel, L. and Yu, A.B.C., 1985. Biofarmasetika dan Farmakokinetika Terapan (edisi kedua).
Universitas Indonesia, Jakarta.
Shargel, L., Pong, S.W. and Yu, A.B.C., 2005. Applied Biopharmaceutics and
Pharmacokinetics. 5th ed, pp. 8, 96-97, 115, Prentice-Hall International Inc., New York.
Swarbick, J. and Boylan, J.C., 2002. Encyclopedia of Pharmaceutical Technology, 2nd edition,
Volume 1, pp. 156-170, Marcel Dekker, New York.
Wagner, J.C., 1971. Biopharmaceutic and Relevant Pharmacokinetics, 1st ed, pp. 115-120,
Drug Intelligence Publishers, Illionis.
Rani,S., Hiremath,R., TextBook of Biopharmaceutical and Pharmacokinetics, Prism Books
Pvt. Ltd., Edn-2000 , pg: 28- 32
Brahmankar, D.M., Jaiswal, S.B., Biopharmaceutics & Pharmacokinetics A Treatise, Vallabh
Prakashan, Edn-2008, pg : 6-59, 75-88
Gibaldi, M. , Pharmacokinetics, Marcel Dekker Inc., New York, 1982 , Edn - 2nd , pg 44 48
D.J. Birkett, Professor of Clinical Pharmacology, Flinders University of South Australia,
Adelaide (Aust Prescr 1994;17:36-8)
http://www.wisegeek.com/what-is-protein-binding.htm
http://www.nottingham.ac.uk/nmp/sonet/rlos/bioproc/plasma_proteins/6.html
etc
BAHAN AJAR : FARMAKOKINETIKA

DOSEN : Farida Lanawati Darsono,S.Si.,M.Sc
Topic 1 : Introduction and Routes of Administration
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
Routes of Administration
Movement of substances across cell membranes
Passive diffusion
Also known as non-ionic diffusion.
It is defined as the difference in the drug concentration on either side of the membrane.
Absorption of 90% of drugs.
The driving force for this process is the concentration or electrochemical gradient.
Facilitated diffusion of glucose
Active transport
Ion pair transport
It is another mechanism is able to explain the absorption of such drugs which ionize at all pH
condition
The sodium-potassium pump
ENDOCYTOSIS
It involves engulfing extracellular materials within a segment of the cell membrane to form a
saccule or a vesicle (hence also called as corpuscular or vesicular transport) which is then pinched
off intracellularly.
Endocytosis
During endocytosis, cells take in substances by invaginating a portion of the plasma membrane,
and forming a vesicle around the substance.
Endocytosis occurs as:
Phagocytosis large particles
Pinocytosis small particles
Receptor-mediated endocytosis specific particles
Exocytosis
Pinocytosis
Receptor-mediated endocytosis
Do not cited this article without permittion from Ms. Farida
rute pemberian obat

nasib obat di dalam tubuh
Pelakuan tubuh terhadap obat ada 4 proses :
1. Absorpsi : masuknya obat kedalam darah (gastrointestinal, bukal,rektal,pulmonal)
2. Distribusi: penyebaran obat keseluruh tubuh mengikuti sistem peredaran darah.
3. Metabolisme : transformasi struktur obat dg jalan oksidasi, reduksi,hidrolisis atau konjugasi
(hepar)
4. Ekskresi : pengeluaran obat dari dalam tubuh (ginjal dan hepar) + kelenjar lain.
Parameter kinetik ,
berguna utk: cara pemakaian obat,monitoring efek obat dan membandingkan kwalitas obat
A. Oral (PO)
Advantages:
Convenient - portable, safe, no pain, easy to take.
Cheap - no need to sterilize (but must be hygienic of course), compact, multi-dose bottles,
automated machines produce tablets in large quantities.
Variety of dosage forms available - fast release tablets, capsules,enteric coated, layered tablets,
slow release, suspensions, mixtures
Disadvantages:
Sometimes inefficient - high dose or low solubility drugs may suffer poor availability, only part
of the dose may be absorbed.
B. Buccal and Sublingual (SL)
Advantages:
First pass - The liver is by-passed thus there is no loss of drug by first pass effect for buccal or
sublingual administration.
Bioavailability is higher.
Rapid absorption - Because of the good blood supply to the area of absorption is usually quite
rapid, especially for drugs with good lipid solubility.
Drug stability - pH in mouth relatively neutral (cf. stomach - acidic). Thus a drug may be more
stable.
Disadvantages:
Holding the dose in the mouth is inconvenient. If any part of the dose is swallowed that portion
must be treated as an oral dose and subject to first pass metabolism.
Usually more suitable for drugs with small doses.
Drug taste may need to be masked.
C. Rectal (PR)
Advantages:
By-pass liver - Some (but not all) of the veins draining the rectum lead directly to the general
circulation thus by-passing the liver. Therefore there may be a reduced first-pass effect.
Useful - This route may be most useful for patients unable to take drugs orally or with younger
children.
Disadvantages:
Erratic absorption - Drug absorption from a supppository is often incomplete and erratic.
Not well accepted. May be some discomfort.

5
D. Intravenous (IV)
Advantages:
Rapid - A quick response is possible. Plasma concentration can be precisely controlled
using IV infusion administration.
Total dose - The whole dose is delivered to the blood stream. That is the bioavailability is
generally considered to 100% after IV administration. Larger doses may be given by IV
infusion over an extended time. Poorly soluble drugs may be given in a larger volume over
an extended time period.
Veins relatively insensitive - to irritation by irritant drugs at higher concentration in dosage
forms.
Disadvantages:
Suitable vein - It may be difficult to find a suitable vein. There may be some tissue damage
at the site of injection.
Maybe toxic - Because of the rapid response, toxicity can be a problem with rapid drug
administrations. For drugs where this is a particular problem the dose should be given as an
infusion, monitoring for toxicity.
Requires trained personnel - Trained personnel are required to give intravenous injections.
Expensive - Sterility, pyrogen testing and larger volume of solvent means greater cost for
preparation, transport and storage.
E. Subcutaneous (SC)
Advantages:
Can be given by patient, e.g. in the case of insulin.
Absorption can be fast from aqueous solution but slower with depot formulations. Absorption is
usually complete. Improved by massage or heat. Vasoconstrictor may be added to reduce the
absorption of a local anesthetic agent, thereby prolonging its effect at the site of interest.
Disadvantages:
Can be painful. Finding suitable sites for repeat injection can be a problem.
Irritant drugs can cause local tissue damage.
Maximum of 2 ml injection thus often small doses limit use.
F.Intramuscular (IM)
Advantages:
Larger volume than SC can be given by IM. They may be easier to administer than IV injections.
A depot or sustained release effect is possible with IM injections, e.g. procaine penicillin.
Disadvantages:
Trained personnel required for injections. The site of injection will influence the absorption,
generally the deltoid muscle provides faster and more complete absorption.
Absorption can be rapid from aqueous solution. Absorption is sometimes erratic, especially for
poorly soluble drugs, e.g. diazepam, phenytoin. The solvent maybe absorbed faster than the drug
causing precipitation of the drug at the site of injection.
Irritiating drug may be painful.
G. Inhalation
May be used for a local effect, e.g. bronchodilators.
Can be used for systemic effect, e.g. general anesthesia.
Rapid absorption by-passing the liver.

6
Absorption of gases is relatively efficient, however solids and liquids are excluded if larger
than 20 micron and even then only 10 % of the dose may be absorbed. Cromolyn is taken as
a powder with 50 % of the particles within the range of 2 to 6 micron. Larger than 20
micron and the particles impact in the mouth and throat. Smaller than 0.5 micron and they
aren't retained. Some portion of the dose may be swallowed
I. Topical or Transdermal
Local effect - ear drops, eye drops or ointment, antiseptic creams and oinments, sunscreens,
callous removal products, etc.
Systemic effect - e.g., nitroglycerin ointment.
Generally absorption is quite slow. Absorption through the skin especially via cuts and
abrasions or from sites were the skin is quite thin can be quite marked. This can be a real
problem in handling toxic materials in the laboratory or pharmacy. This can also be a
serious problem with garden chemicals.
An occlusive dressing may be used to improve absorption.
Transdermal patches can provide prolonged or controlled (iontrophoresis) drug delivery.
J. Other ROA's
Other routes of administration include:
nasal, some systemic absorption has been demonstrated for propranolol and some low dose
hormones;
intra-arterial for cancer chemotherapy to maximize drug concentrations at the tumor site;
intrathecal directly into the cerebrospinal fluid.
Others routes with limited systemic absorption but with local utility include topical, ocular,
aural, vaginal, urethral and intrasynovial

Topic 2 : Drug Distribution

point
To understand and describe the process by which drugs are distributed throughout the body
To understand the effect of protein binding on drug distributed
drug distribution patterns: 4 types
The drug may remain largely within the vascular system
(ex: dextran ~plasma/drugs which stronglybound tp plasma)
Some low molecular weight water soluble compounds
(become uniformly distributed throughout the body water) - (ex: ethanol / a few sulfonamide)
A few drugs are concentrated specifically in one or more tissues that may or may not be the site
of action
(ex:iodine~thyroid glands/chloroquine~liver 1000x than present in
plasma/tetracycline
~irreversible bound to bone & developing teeth )
Most drugs exhibit a non-unifrorm distribution in the body with variations that are largely
determined by the ability to pass through membranes and their lipid/water solubility
(ex: the highest concentrations are often present in the : kidney, liver, intestine)
Nb:
pattern 4 is the most common being a combination of patterns 1,2 and 3

Distribution of various substances within the body is NOT HOMOGENOUS
definition : distribution
Distribution: Movement of drug from the central compartment (blood) to peripheral
compartments (tissues) where the drug is present.
Distribution of a drug from systemic circulation to tissues is dependent on lipid solubility ,
ionization, molecular size , binding to plasma proteins , rate of blood flow and special
barriers
The body compartments include extracellular (plasma, interstitial) and intracellular which are
separated by capillary wall and cell membrane
Distribution: the passage of drugs from blood to tissues.
Distribution ---- where do drugs go?
Once a drug has gained excess to the blood stream, the drug is subjected to a number of processes
called as Disposition Processes that tend to lower the plasma concentration.
1. Distribution which involves reversible transfer of a drug between compartments.
2. Elimination which involves irreversible loss of drug from the body. It comprises of
biotransformation and excretion.
Diffusion and hydrostatic pressure
a. Passive diffusion : gradient conc --- ficks law
b. Hydrostatic pressure :
(*) a pressure gradient between the arterial and of the capillaries entering the tissue and the
venous capillaries leaving the tissue
(*) resonsible for penetration of water soluble drugs into spaces, between endothelial celss &
possible into lymph

8
The important factors in dtermining the rate of drug diffusion are :

The membranes thickness
Diffusion coefficient of the drugs
Concentration gradient across the capillaries membranes
Factor affecting drug distribution
a. Rate of distribution :
membranes permeability
blood perfussion
b. Extent of distribution
lipid solubility
pH pka
plasma protein binding
intracellular binding
c. Tissue size
d. Tissue storage
Rate limiting of distribution (tahap penetu kecepatan distribusi)
a. Drug --- diffuse rapidly -----blood flow : perfussion rate limited (flow limited)
b. Drug --- slow diffusion -----membrane cell : permeability rate limited (diffusion)
Redistribution
9 Highly lipid soluble drugs when given by i.v. or by inhalation initially get distributed to
organs with high blood flow, e.g. brain, heart, kidney etc.
9 Later, less vascular but more bulky tissues (muscles,fat) take up the drug and plasma
concentration falls and drug is withdrawn from these sites.
9 If the site of action of the drug was in one of the highly perfused organs, redistribution
results in termination of the drug action.
9 Greater the lipid solubility of the drug, faster is its redistribution.
Vd =
Dose
Plasma concentration
Volume of Distribution
Volume of Distribution (Vd) [ml or l]:
= Amount of drug in the body [mg] / drug concentration plasma [mg/ml]
Volume of Distribution (Vd): apparent volume of body water that drug appears to distribute
into to produce a drug concentration equal to that in the blood.
Apparent and hypothetical volume in which the drug is dispersed.
Vd is an apparent volume (volume that the drug must be distributed in to produce measured
plasma concentration
Drug with near complete restriction to plasma compartment would have Vd = plasma volume
(.04 L/kg) = 2.8 L/70 kg patient
But: Many drugs are highly tissue bound => large Vd
e.g. Chloroquine: Vd = 13,000 L

9
Distribution
Membrane permeability
cross membranes to site of action
Plasma protein binding
bound drugs do not cross membranes
malnutrition = albumin = free drug
Lipophilicity of drug
lipophilic drugs accumulate in adipose tissue
Volume of distribution
Factors affecting the equilibrium distribution of drugs across the compartments
1. Membrane-impermeant drugs will be excluded from the intracellular volume (Example:
Lithium)
2. Lipophilic drugs will be enriched in the fat tissue (example: Thiopental see later)
3. Drugs with a high degree of protein binding will be more concentrated in the plasma (the
intravascular volume) than in the interstitial fluid
To be absorbed and distributed, drugs must cross barriers (membranes) to enter and leave the
blood stream.
Body contains two type of barriers which are made up of epithelial or endothelial cells:
A. External (Absorption Barriers):
Keratinized epithelium (skin), ciliated epithelium (lung), epithelium with microvilli (intestine)
These epithelial cells are connected via zonulae occludens (tight junctions) to create an
unbroken phospholipid bilayer.
Therefore, drugs MUST cross the lipophilic membrane to enter the body (except parenteral)
B. Internal (Blood-Tissue Barriers):
Drug permeation occurs mostly in the capillary bed, which is made up of endothelial cells
joined via zonulae occludens.
Blood-Tissue Barrier is developed differently in various capillary beds:
1. Cardiac muscle: high endo- and transcytotic activity-> drug transport via vesicles
2. Endocrine glands, gut: Fenestrations of endothelial cells (=pores closed by diaphragms)
allow for the passage of small molecules.
3. Liver: Large fenestration (100 nm) without diaphragms-> drugs exchange freely between
blood and interstitium
4. CNS, placenta: Endothelia lack pores and possess only little trans-cytotic activity-> drugs
must diffuse transcellularly, which requires specific physicochemical properties ->
Barriers are very restrictive, permeable only to certain types of drugs.
Plasma: 4 liters.
Interstitial volume: 10 liters.
Intracelullar volume: 28 liters
Plasma compartment
(*) Vd: around 5 L.
(*) Very high molecular weight drugs, ordrugs that bind
to plasma proteins excesively
Example: heparin 4L (3-5)
Extracellular fluid
(*) Vd: between 4 and 14 L.
(*) Drugs that have a low molecular weight but are hydrophilic.
Example : Atracuronium 11 L (8-15)
10 without permittion from Ms. Farida

Do not cited this article
Vd equal or higher than total body water
Diffusion to intracelullar fluid . Vd equal to total body water.

Ethanol 38 L (34-41)
Alfentanyl 56 L (35-77)
Drug that binds strongly to tissues. Vd higher than total body water.
Fentanyl: 280 L
Propofol: 560 L
Digoxin:385 L
Key factor in the onset of drug action-Body Water Compartments

BODY WATER COMPARTMENTS: 50Kg & 100Kg ---- (110 lb) (220 lb)
Total body water (60% body weight) = 0.6 L/Kg, 30 L & 60 L
Extracellular (20% body weight) = 0.2L/Kg, 10 L & 20 L
Plasma (4% body weight) = 0.04L/Kg, 2 L & 4 L
Interstitial (16% body weight) = 0.16L/Kg, 8 L & 16 L
Intracellular (40% body weight) = 0.4 L/Kg, 20 L & 40 L
Drugs which bind selectively to Plasma proteins e.g. Warfarin have Apparent volume of
distribution smaller than their Real volume of distribution.
The Vd of such drugs lies between blood volume and total body water i.e. b/w 6 to 42 liters.
Drugs which bind selectively to Extravascular Tissues e.g. Chloroquine have Apparent volume
of distribution larger than their Real volume of distribution.
The Vd of such drugs is always greater than 42 liters.
Body fluids
water sources (water drinking/water contained in food/metabolism to CO2 & H2O)
water losses (urinary loss, fecal loss, insensible H2O loss, sweat loss, pathological loss)
electrolytes (electrolyte losses: renal excretion, stol losses, sweating, abnormal routes
(vomit & diarrhea)
Differences In Drug Distribution Among Various Tissues Arises Due To a Number of Factors:
Tissue Permeability of the Drug
a. Physiochemical Properties of the drug like Molecular size, pKa and o/w Partition
coefficient.
b. Physiological Barriers to Diffusion of Drugs.
Organ / Tissue Size and Perfusion Rate
Binding of Drugs to Tissue Components (Blood components, Extravascular Tissue Proteins)
Miscellaneous Factors (Age, Pregnancy, Obesity, Diet, Disease states, and Drug Interactions)
Tissue Permeability of the Drugs depend upon:

1. Rate of Tissue Permeability, and
2. Rate of Blood Perfusion.
The Rate of Tissue Permeability, depends upon Physiochemical Properties of the drug as well
as Physiological Barriers that restrict the diffusion of drug into tissues.
Physiochemical Properties that influence drug distribution are:
i. Molecular size,
ii. pKa, and
iii. o/w Partition coefficient.
11
Drugs having molecular wt. less than 400 daltons easily cross the Capillary Membrane to
diffuse into the Extracellular Interstitial Fluids.
Now, the penetration of drug from the Extracellular fluid (ECF) is a function of : Molecular Size:
Small ions of size < 50 daltons enter the cell through Aq. filled channels where as larger size
ions are restricted unless a specialized transport system exists for them.
Ionisation:
A drug that remains unionized at pH values of blood and ECF can permeate the cells more
rapidly.
Blood and ECF pH normally remains constant at 7.4, unless altered in conditions like Systemic
alkalosis/acidosis.
PENETRATION OF DRUGS THROUGH BLOOD BRAIN BARRIER
A stealth of endothelial cells lining the capillaries.
It has tight junctions and lack large intra cellular pores.
Further, neural tissue covers the capillaries.
Together , they constitute the BLOOD BRAIN BARRIER.
Astrocytes : Special cells / elements of supporting tissue are found at the base of endothelial
membrane.
The blood-brain barrier (BBB) is a separation of circulating blood and cerebrospinal fluid
(CSF) maintained by the choroid plexus in the central nervous system (CNS).
Since BBB is a lipoidal barrier
It allows only the drugs having high o/w partition coefficient to diffuse passively where
as moderately lipid soluble and partially ionized molecules penetrate at a slow rate.
Endothelial cells restrict the diffusion of microscopic objects (e.g. bacteria ) and large or
hydrophillic molecules into the CSF, while allowing the diffusion of small hydrophobic
molecules (O2, CO2, hormones).
Cells of the barrier actively transport metabolic products such as glucose across the barrier with
specific proteins.
Various approaches to promote crossing BBB:
Use of Permeation enhancers such as Dimethyl Sulfoxide.
Osmotic disruption of the BBB by infusing internal carotid artery with Mannitol.
Use of Dihydropyridine Redox system as drug carriers to the brain ( the lipid soluble
dihydropyridine is linked as a carrier to the polar drug to form a prodrug that rapidly crosses
the BBB )
PENETRATION OF DRUGS THROUGH PLACENTAL BARRIER
Placenta is the membrane separating Fetal blood from the Maternal blood.
It is made up of Fetal Trophoblast Basement Membrane and the Endothelium.
Mean thickness in early pregnancy is (25 ) which reduces to (2 ) at full term.
Many drugs having mol. wt. < 1000 Daltons and moderate to high lipid solubility e.g. ethanol,
sulfonamides, barbiturates, steroids, anticonvulsants and some antibiotics cross the barrier by
simple diffusion quite rapidly .
Nutrients essential for fetal growth are transported by carrier mediated processes.

12
Blood Cerebrospinal Fluid Barrier:

The Cerebrospinal Fluid (CSF) is formed mainly by the Choroid Plexus of lateral, third and
fourth ventricles.
The choroidal cells are joined to each other by tight junctions forming the Blood CSF barrier
which has permeability characteristics similar to that of BBB.
Only high lipid soluble drugs can cross the Blood CSF barrier.
Blood Testis Barrier:
It has tight junctions between the neighboring cells of sertoli which restricts the passage of
drugs to spermatocytes and spermatids.
Organ / Tissue Size and Perfusion Rate
Perfusion Rate is defined as the volume of blood that flows per unit time per unit volume of the
tissue.
Greater the blood flow, faster the distribution.
Highly perfused tissues such as lungs, kidneys, liver, heart and brain are rapidly equilibrated
with lipid soluble drugs.
The extent to which a drug is distributed in a particular tissue or organ depends upon the size of
the tissue i.e. tissue volume.
Miscellaneous Factors
Diet: A Diet high in fats will increase the free fatty acid levels in circulation thereby affecting
binding of acidic drugs such as NSAIDS to Albumin.
Obesity: In Obese persons, high adipose tissue content can take up a large fraction of lipophilic
drugs.
Pregnancy: During pregnancy the growth of the uterus, placenta and fetus increases the volume
available for distribution of drugs.
Disease States: Altered albumin or drug binding protein conc.
Altered or Reduced perfusion to organs /tissues
Altered Tissue pH
WHAT ARE THE DETERMINANTS OF WHERE DRUGS GO?
Determinants of Drug Distribution:
Organ blood flow
Barriers to drug diffusion
Adipose tissue
Tissue protein binding
Plasma protein binding
Drug transport
Ion trapping
WHAT IS THE EFFECT OF ORGAN BLOOD FLOW ON DRUG DISTRIBUTION?
Organs with high blood flow will have larger amounts of drug delivered to them per unit time.
Organs with high blood flow will experience initial high concentrations of drug, but these high
concentrations will diminish as the drug is redistributed throughout the body to sites with lower
blood flow.
Organs with high blood flow will experience larger initial effects.
Many sedative/hypnotics, such as benzodiazepines
(e.g., diazepam,[Valium]) will produce initial, but short-lived, profound CNS effects
following IV administration.
13
WHAT IS THE EFFECT OF BARRIERS TO DRUG DIFFUSION ON DRUG

DISTRIBUTION?
Most capillaries have pores between the endothelial cells lining the capillaries.
These pores allow for rapid diffusion of most drugs into the interstitial space.
In some capillary beds, however, the endothelial cells are closely connected by tight
junctions, and such capillaries do not have pores between the endothelial cells.
DISTRIBUTION?
In capillaries with tight junctions, drug molecules must diffuse across (transcellular), rather than
around (paracellular) the endothelial cells.
Only lipophilic drugs rapidly diffuse across capillary beds with tight junctions, whereas
hydrophilic drugs are mostly excluded.
DISTRIBUTION?
The blood-brain barrier (BBB) is a special case:
Capillaries in brain have tight junctions that contribute to the BBB.
Capillaries in brain are wrapped by pericapillary glial cells that further contribute to the BBB.
The endothelial cells in brain capillaries have P-glycoprotein that pumps drugs out of
endothelial cells, and this also contributes to the BBB.
In general, the BBB restricts the movement of hydrophilic drugs into brain; however, the BBB
is broken by ischemia and inflammation.
The BBB can be exploited to develop drugs with reduced CNS adverse effects.
WHAT IS THE EFFECT OF ADIPOSE TISSUE ON DRUG DISTRIBUTION?
Lipophilic drugs will distribute into adipose (fat) tissue.
Distribution of lipophilic drugs into fat may necessitate a larger initial bolus of drug to achieve
the desired effect.
Large depots of drug in fat may necessitate a longer period of time for drug to be removed
from the body.
The distribution of lipophilic drugs will be different in thin versus obese patients.
WHAT IS THE EFFECT OF TISSUE PROTEIN BINDING ON DRUG DISTRIBUTION?
Some drugs are highly bound to tissue proteins.
Binding of drugs by tissue may necessitate a larger initial bolus of drug to achieve the desired
effect.
Large depots of drug in tissue may necessitate a longer period of time for drug to be removed
from the body.
WHAT IS THE EFFECT OF PLASMA PROTEIN BINDING ON DRUG DISTRIBUTION?
Some drugs are highly bound (> 90%) to plasma proteins.
Acid drugs bind to albumin and basic drugs bind to alpha1-acid glycoprotein.
Binding of drugs by plasma proteins limits the distribution of drugs out of the vascular
compartment, necessitating more drug initially to achieve the desired effect.
Binding of drugs may limit the delivery of drugs to drug elimination mechanisms (for example
excretion by the kidney or metabolism by the liver), and this increases the time required for the
drug to be removed from the body.

14
WHAT IS THE EFFECT OF PLASMA PROTEIN BINDING ON DRUG DISTRIBUTION?

Displacement of a highly plasma-protein bound drug by another drug may lead to drug-drug
interactions because of a rapid increase in the availability of free (unbound) drug.
Displacement of unconjugated bilirubin from albumin by drugs may precipitate bilirubin
encephalopathy in newborns.
WHAT IS THE EFFECT OF DRUG TRANSPORT ON DRUG DISTRIBUTION?
Transport mechanisms may increase or decrease the distribution of drugs to certain tissues.
For example, most diuretics are transported by the proximal tubules into the nephron, a
process that delivers the diuretics to their site of action.
Competition for transport may result in drug-drug interactions.
For example, probenecid ( a drug used for gout) blocks the transport of diuretics into the
proximal tubule and thereby markedly blunts the effects of diuretics on salt and water
excretion.
WHAT IS THE EFFECT OF I0N TRAPPING ON DRUG DISTRIBUTION?
Ion trapping can be used to distribute drugs into the urinary compartment to increase the urinary
excretion of poisons.
Example: Alkalinization of the urine with systemic administration of sodium bicarbonate is
useful for the treatment of overdoses of aspirin and phenobarbital.
Example: Acidification of the urine with systemic administration of ammonium chloride is
useful for the treatment of amphetamine overdoses.

15

Topic 3 : Drug Accumulation in Lysosom

Steps in lysomal formation
1. The ER and Golgi apparatus make a lysosome
2. The lysosome fuses with a digestive vacuole
3. Activated acid
4. hydrolases digest the contents
Early endosome : pH 6.5-6 and sorting endosome
Late endosome : pH 5.5-5
Lysosome
: pH 5-4.5
Lysosomes are vesicles produced by the Golgi aparatus.

Lysosomes contain hydrolytic enzymes and are involved in intracellular digestion.
Protein rich membranes (Lamp/Limp family of glycoproteins)
Unusual lipids
1. lyso-bisphosphatidic acid
2. thought to protect lysosomal membrane lipids from action of lumenal lipases
Multivesicular bodies (late endosomes/lysosomes)
1. invagination of the limiting membrane
2. forms internal membranes
TM proteins can segregate into limiting or internal membranes limiting membrane can be
recycled, internal is not
Lysosomes receive cellular and endocytosed proteins and lipids that need digesting.
The metabolites that result are transported either by vesicles or directly across the membrane
Ion trapping: lysosomes

Lysosomes are membrane-enclosed organelles
Contain a range of hydrolytic enzymes responsible for autophagic and heterophagic digestion
Abundant in Lung, Liver, kidney, spleen with smaller quantities in brain, muscle
pH maintained at ~5 (4.8).
Passive process:
BH+ ====base ====Bun === BH+ ---- lysosome (acidic)
equilibrium
result
: [Bun] inside = [Bun] outside

[BH+] inside > [BH+] outside
: acumulation
pH & pka :
A- ===HA ====HA ====A- ---- lysosome
equilibrium
result
: [A-] outside >[A-] inside

: no acumulation
16
Weak base ---- ion trapping ------- accumulation (Vd >>>)

BH+ ====BH+ ====B === BH+ ---- BH+
dibasic/ion trapping
Lipophilic cationic drugs increase the permeability of lysosomal membranes in a cell culture
system
Lysosomes accumulate many drugs several fold higher compared to their extracellular
concentration.
This mechanism is believed to be responsible for many pharmacological effects.
So far, uptake and release kinetics are largely unknown and interactions between
concomitantly administered drugs often provoke mutual interference. In this study, we
addressed these questions in a cell culture model.
The molecular mechanism for lysosomal uptake kinetics was analyzed by live cell
fluorescence microscopy in SY5Y cells using four drugs (amantadine, amitriptyline,
cinnarizine, flavoxate) with different physicochemical properties.
Drugs with higher lipophilicity accumulated more extensively within lysosomes, whereas a
higher pKa value was associated with a more rapid uptake.
The drug-induced displacement of LysoTracker was neither caused by elevation of intralysosomal pH, nor by increased lysosomal volume.
We extended our previously developed numerical single cell model by introducing a dynamic
feedback mechanism.
The experimental data and results from the numerical model lead to the conclusion that intralysosomal accumulation of lipophilic xenobiotics enhances lysosomal membrane permeability.
Manipulation of lysosomal membrane permeability might be useful to overcome, for example,
multi-drug resistance by altering subcellular drug distribution
(Journal of Cellular Physiology, Volume 224, Issue 1, pages 152164, July 2010)
Accumulation of Drugs in Tissues

Drugs need to achieve an adequate concentration in their target tissues in order to exert
pharmacological action.
The concentration of a drug at any moment and in any region of the body depends on
translocation of the drug molecules and the chemical transformations they undergo due to
metabolic action.
This article focuses on movement of drug molecules across cell barriers, absorption,
distribution, and various approaches for drug delivery
(Pharmaceutical Sciences Encyclopedia: Drug Discovery, Development, and Manufacturing, Published
Online: 15 MAR 2010,DOI: 10.1002/9780470571224.pse043)
The role of lysosomes in the cellular distribution of thioridazine and potential drug interactions
The purpose of the present study was to investigate the contribution of lysosomal trapping to the total
tissue uptake of thioridazine and to potential drug distribution interactions between thioridazine and
tricyclic antidepressants (imipramine, amitriptyline) or selective serotonin reuptake inhibitors (SSRIs;
fluoxetine, sertraline).
The experiment was carried out on slices of various rat tissues as a system with intact lysosomes.
The results show that the contribution of lysosomal trapping to the total tissue uptake of thioridazine is
as important as phospholipid binding.
17
A high degree of dependence of thioridazine tissue uptake on the lysosomal trapping is the cause of
substantial distributive interactions between thioridazine and the investigated antidepressants at the
level of cellular distribution.
Thioridazine and the antidepressants, both tricyclic and SSRIs, mutually decreased their tissue uptake.
Intracellular Distribution-based Anticancer Drug Targeting: Exploiting a Lysosomal

Acidification Defect Associated with Cancer Cells
The potency of antidepressants to decrease thioridazine uptake was similar to that of lysosomal
inhibitors.
In general, the observed interactions between thioridazine and antidepressants occurred only in
those tissues in which thioridazine showed lysosomotropism (the lungs, liver, kidneys, brain,
and muscles) but were not observed in the presence of ammonium chloride.
The above finding provides evidence that the interactions proceeded at the level of lysosomal
trapping.
In the adipose tissue and heart no lysosomal trapping of thioridazine was detected and those
tissues were not the site of such an interaction.
Since the organs and tissues involved in the distributive interactions constitute a major part of
the organism and take up most of the total drug in the body, the interactions occurring in them
may cause a substantial shift of the drugs to organs and tissues poor in lysosomes, e.g. the
heart and muscles.
(Toxicology and applied pharmacology ISSN 0041-008X CODEN TXAPA9, 1999, vol. 158, no2, pp. 115-124 (1
p.1/4) , Elsevier, Amsterdam, PAYS-BAS (1959) (Revue))
nano-polymer
the pH is slightly depressed in early to mid stage endosomes even before material is delivered to
the lysosome.
There are a number of materials that can respond to changes in acidity, for example simple
polymers with pendant carboxyl groups.
At hight pH, above the polymer's pKa, the carboxyl groups are all ionised.
The chain as a whole has a large negative charge, which repels neighbouring chains, but attracts
water molecules which hydrogen bond into the structure.
As the pH is lowered, the proton concentration increases.
At some critical pH - equivalent to the polymer's pKa, the carboxyl groups are protonated, and
loose their charge.
The polymer chain become a lot less hydrophilic, and has a tendency to stick to itself, adopting a
clumped up or globular conformation,
(http://www.nanofolio.org/research/paper08.php)
Intracellular Distribution-based Anticancer Drug Targeting: Exploiting a Lysosomal
Acidification Defect Associated with Cancer Cells
The therapeutic usefulness of anticancer agents relies on their ability to exert maximal toxicity
to cancer cells and minimal toxicity to normal cells.
The difference between these two parameters defines the therapeutic index of the agent.
Towards this end, much research has focused on the design of anticancer agents that have
optimized potency against a variety of cancer cell types; however, much less effort is spent on
the design of drugs that are minimally toxic to normal cells.
We
have previously described a concept for a novel drug delivery platform that relies on the
propensity of drugs with optimal physicochemical properties to distribute differently in normal

versus cancer cells due to differences in intracellular pH gradients.
18
Specifically, we demonstrated in vitro that certain weakly basic anticancer agents had the
propensity to distribute to intracellular locations in normal cells that prevent interaction with the
drug target, and to intracellular locations in cancer cells that promote drug-target interactions.
We refer to this concept broadly as intracellular distribution-based drug targeting.
Here we will discuss current in vivo work from our laboratory that examined the role of
lysosome pH on the intracellular distribution and toxicity of inhibitors of the Hsp90 molecular
chaperone in mice.
(Molecular and Cellular Pharmacology, Vol 2, No 4 (2010))
Lysosomes Contribute to Anomalous Pharmacokinetic Behavior of Melanocortin-4 Receptor
Agonists
Weakly basic drugs with optimal physicochemical properties can be extensively sequestered
into lysosomes according to a pH-partitioning type mechanism.
When administered orally in animals, this particular sequestration event can manifest itself in
long term retention in the liver and negligible levels in blood.
This work revealed the mechanism for liver retention and provided a rational platform for the
design of a new analog with decreased liver accumulation and better opportunity for
pharmacokinetic analysis and therapeutic activity.
(Pharmaceutical Research, Volume 24, Number 6, 1138-1144, DOI: 10.1007/s11095-007-92)

19

Topic 4 : Drug Protein Binding

Ikatan O-P
Merupakan suatu ikatan yg terbentuk dari hasil interaksi obat dg protein di dalam plasma
Merupakan suatu ikatan yg menghasilkan kompleks makromolekul
Sifat ikatan O-P
a. Reversibel:
* ikatan kinia yg lemah (ikt. Hidrogen/gaya van der waals)
* contoh : gol asam amino --- penyusun rantai protein
b. Irreversibel:
* ikatan kimia yg kuay (ikt. Kovalen)
* timbul toksisitas
* contoh :
a. jangka pendek : parasetamol --- hepatotoksisitas
b. jangka panjang : parasetamol karsinogenik kimia
Protein binding generally refers to the binding of a drug to proteins in blood plasma.
The interaction can also be between the drug and tissue membranes, red blood cells, and other
components of the blood.
The amount of drug bound to protein determines how effective the drug is in the body.
The bound drug is kept in the blood stream while the unbound components of the drug may be
metabolized or extracted, making them the active part of the drug. So, if a drug is 95% bound to
a binding protein and 5% is free, that means that 5% of the drug is active in the system and
causing pharmacological effects.
Protein binding is often reversible and thus creates a chemical equilibrium, in which the
chemical reaction can go backward and forward with no net change in reactants and products.
This means that a cell that is effective at extracting the unbound drug may extract more of the
drug as it disassociates in the course of achieving equilibrium.
The equation for reversible protein binding is: Protein + drug Protein-drug complex
The proteins commonly involved with protein binding are albumin, lipoproteins, and alglycoprotein.
A protein is a chain of amino acids joined by peptide bonds.
Acidic drugs will tend to bind to albumin, which is basic and basic drugs will primarily bind to
al-glycoprotein, which is acidic.
Acidic drugs may also bind to lipoproteins if the albumin is saturated. Lipoprotein binding is
not binding in the strict sense of the term; it is closer to dissolving and is common in lipid
soluble drugs.
A drug that binds to tissue often binds to melanin-rich tissue or DNA.
The amount of protein binding and the fraction unbound, written as the concentration of
unbound drug over the total concentration of the drug, depends on several factors.
It is determined by the drugs affinity for the protein, the concentration of the binding protein,
and the concentration of the drug relative to the binding protein.
This is important when considering other medications that a patient might be on because certain
proteins may already be saturated, which would affect the amount of free drug and possibly
change the desired pharmacologic effects.
20
For example, if drug A saturated a certain binding protein and then drug B was not able to bind
to that protein, then there would be a higher concentration of unbound drug B. Drug B could
also competitively displace drug A from the binding protein, thus raising the unbound fraction
of drug A.
This process happens fairly quickly, in minutes to hours, and both scenarios could have adverse
effects. Many drugs, however, have different binding proteins, different binding sites on a
protein, or are not present in high enough relative concentration to saturate the proteins, and so
do not compete with the other drug or drugs in use.
Likewise, the ability of the body to extract the drug can affect the drugs clearance into the
body.
Renal failure and liver disease often negatively impact the bodys ability to extract the unbound
drug.
For these reasons, it is important to consider previous medical issues, the total concentration of
the drug, the unbound fraction of the drug, and any other medications a patient may be taking.
So, if a drug is 95% bound to a binding protein and 5% is free, that means that 5% of the drug
is active in the system and causing pharmacological effects.
Protein binding is often reversible and thus creates a chemical equilibrium, in which the
chemical reaction can go backward and forward with no net change in reactants and products.
In addition to being a unique structure, a bacterial protein also has the ability to bind with other
proteins.
Protein binding involves the formation of very strong links between two different proteins.
(http://www.wisegeek.com/what-is-protein-binding.htm)
Membrane Proteins
An enzyme called protein kinase C is another interior peripheral membrane protein.
It initiates signaling pathways inside the cell.
Peripheral membrane proteins do not interact with the non-polar region of the cell
membrane.
Both structurally and functionally, they are integral parts of the membranes of cells.
Each integral membrane protein molecule has an intricate relationship with the membrane
within which it is situated.
Various routes are used to administer drugs but in most cases drugs reach their site of action via
the systemic circulation.
Once within the circulation a drug is clearly not confined to its intended site of action.
Instead it is distributed widely throughout the body.
At this point you may have anticipated some important questions:
How is the drug carried in the blood? Is the entire drug free to exert an effect?
Can the presence of one drug in the circulation affect another?
To begin to understand the answer to these questions we need first of all to think about plasma
proteins
(http://www.nottingham.ac.uk/nmp/sonet/rlos/bioproc/plasma_proteins/6.html)

21
Plasma Proteins
Suppose we take a sample of blood and mix it in a tube with an anticoagulant to stop it clotting,
before spinning it in a centrifuge.
What now will our sample look like?
The cellular components will have sunk to the bottom of the tube they form about 45% of the
sample.
The remaining 55% is the liquid we call plasma.
What does plasma consist of?
Most of it is water about 92%, whilst plasma proteins form about 7%.
The remaining 1% is other dissolved solutes such as inorganic ions.
Types of Plasma Protein
Most, but not all, plasma proteins are manufactured in the liver including albumins.
These are the most abundant and form about 60% of all plasma proteins.
They contribute to osmotic pressure, help to control water balance and are involved in the
transport of substances in blood including drugs.
Globulins (globular proteins) form 35% of the whole and include antibodies, whilst others have
transport functions.
Approximately 4% of plasma proteins, such as fibrinogen, have a clotting function whilst the
remaining less than 1% are regulatory such as metabolic enzymes
Drugs and Plasma Proteins
The main influence of plasma proteins on drugs is in their distribution.
The most important plasma proteins in this context are albumin, acid-glycoprotein and betaglobulin.
Once a drug has been absorbed into the circulation it may become attached (we say bound) to
plasma proteins.
However this binding is rapidly reversible and non-specific that is many drugs may bind to
the same protein.
It is important to recognise that plasma proteins do not represent target tissues and drug binding
produces no physiological effect.
Drugplasma protein binding forms a "reservoir" of drug, but only the free (unbound) drug is
available to the tissues to exert a therapeutic
Jenis protein yg terikat dg obat
Albumin
1-acid glycoprotein (AAGP)
lipoprotein
albumin
Disintesi di hati
BM= 65.000-69.000
Terdistribusi di plasma dan cairan ekstraseluler
T eliminasi = 17-18 hari
Konsentrasi normal : 3,5 5,5 % atau 4,5 mg/dL
Fungsi :
1. mengatur tekanan osmotis darah
2. trasnpor komponen endogenous dan exogenous (ex: free fatty acid, bilirubin, hormon)
22
Bersifat selektif
Terdiri dari 6 tempat ikatan
* 2 --- mengikat kuat --- asam lemah
* 2 --- mengikat bilirubin
* 1 --- mengikat obat (site 1)
* 1 --- mengikat obat (site 2)
Memiliki pH = (-) ve charge
Mengikat obat yg bersifat asam lemah
Low binding afinity & high binding capacity
AAGP
Is an acute phase reaction which has one binding site selective for basic drug
BM = 44.000
Konsentrasi dalam plasma = 0,4 1%
Terutama mengikat obat yg bersifat basa (kationik)
Level konsentrasi AAGP akan mengikat pada kondisi:
a. trauma
b. kehamilan
c. myocardial infraction
d. chronic RF
e. malignancy
lipoprotein
Merupakan komplek makromolekul antara lemak dg protein
Berdasarkan density dan pemisahan secara ultrasentrifuse terdiri dari:
1. VLDL
2. LDL
3. HDL --- good protein
Berfungsi transpor lemak plasma dan ikatan obat (jika albumin jenuh) --- siklosporin,
trigliserida, kolesterol
Memiliki non polar lipid core :
1. ester kolesterol & trigliserida
2. fosfolipid & free kolesterol
3. apo-lipoprotein
Binds (terikat) highly with lipoprotein drug
Lipoprotein level changes depend on fasted or fed state
Competition binding with albumin
RBCs (Red Blood Cells)
Mengikat kedua komponen endogenous & exogenous
Meliputi 45 % dr volume darah
Tidak terlalu berpengaruh pada Vd

23
Cara evaluasi OP
Tujuan : untuk mengetahui sejauh mana ikatan obat dengan protein yg terjadi
Umumnya secara : in vitro
Perangkat yg diperlukan :
a. instrumen
b. protein yg dimurnikan ---albumin
c. membran semipermiabel
Metode penentuan :
a. langsung : uv-vis, NMR, dll
b. dialisis : ultracentrifugation
Keuntungan : pengukuran lebih mudah, hemat waktu, peralatan umum
Kerugian : biaya mahal
Faktor yg mempengaruhi OP
1. Obat :
* Sifat fisikokimia
* [C] total dalam tubuh
2. Afinitas obat terhadap protein:
* tetapan asosiasi (ka)
3. Interaksi obat:
* kompetisi : obat vs zat lain
* perubahan protein (sbg substrat)
4. Patofisiologis pasien:
* kelainan liver atau ginjal, dll
5. Protein
Factor affecting drug protein binding
1. factor relating to the drug
a) Physicochemical characteristic of drug
b) Concentration of drug in the body
c) Affinity of drug for a particular componant
2. factor relating to the protein and other binding componant
a) Physicochemical characteristic of the protein or binding componant
b) Concentration of protein or binding componant
c) Num. Of binding site on the binding site
3. drug interation
4. patient related factor
Drug related factor
Physicochemical characteristics of drug

Protein binding is directly related to lipophilicity
lipophilicity =
the extent of binding
9 e.g. The slow absorption of cloxacilin in compression to ampicillin after i.m. Injection is
attributes to its higher lipophilicity it binding 95% letter binding 20% to protein
9 Highly lipophilic thiopental tend to lacalized in adipose tissue .
9 Anionic or acidic drug like . Penicillin , sulfonamide bind more to HSA
9 Cationic or basic drug like . Imepramine alprenolol bind to AAG

24
CONCENTRATION OF DRUG IN THE BODY

The extent of drugprotein binding can change with both change in drug and protein
concentration
The con. of drug that binding HSA does not have much of an influence as the thereuptic
concentration of any drug is insufficient to saturate it
Eg. Thereuptic concentration of lidocaine can saturate AAG with which it binding as the
con. Of AAG is much less in compression to that of HSA in blood
DRUG PROTEIN / TISSUE AFFINITY
Lidocaine have greater affinity for AAG than HSA
Digoxin have greater affinity for protein of cardiac muscle than skeleton muscles or plasma
Protein or tissue related factor

Physicochemical properity of protein / binding componant lipoprotein or adipose tissue tend
to bind lipophilic drug by dissolving them to lipid core .
The physiological pH determine the presence of anionic or cationic group on the albumin molecule
to bind a verity of drug
Concentration of protein / binding componant
Mostly all drug bind to albumin b/c it present a higher concentration than other protein
Number of binding sites on the protein
Albumin has a large number of binding site as compare to other protein and is a high capacity
binding component
Drug interaction
a. Competition b/w drug for binding site (displacement interaction )
When two or more drug present to the same site , competition b/w them for interaction with
same binding site . If one of the drug (A) is bound to such a site , then administration of the
another drug (B) having high affinity for same binding site result in displacement of drugs (A)
from its binding site. This type of interaction is known as displacement interaction. Wher drug
(A) here is called as the displaced drug and drug (B) as the displacer .
Eg. Phenylbutazone displace warferin and sulfonamide fron its binding site
b. Competition b/w drug and normal body constituent
The free fatty acids are interact to with a number of drug that bind primarily to HSA . When free
fatty acid level is increase in several condition fasting , - pathologic diabeties , myocardial
infraction , alcohol abstinence the fatty acid which also bind to albumin influence binding of
several drug
binding diazepam
- propanolol
binding - warferin
Acidic drug like sod. Salicilate , sod . Benzoate , sulfonamide displace bilirubin from its albumin
binding site result in neonate it cross to BBB and precipitate toxicity (kernicterus )

25
Disease state
Disase
Influence on plasma
protein
Renal failure
(uremia)
albumin content
Hepatic failure
albumin
synthesis
Inflammatory state
(trauma , burn, infection )
AAG levels
Influence on protein drug

binding
Decrease binding of acidic drug ,

neutral or basic drug are
unaffected
Decrease binding of acidic drug
,binding of basic drug is
normal or reduced depending
on AAG level.
Increase binding of basic drug ,
neutral and acidic drug
unaffected
Hal-hal yg harus diperhatikan dalam evaluasi OP

Kondisi setimbang antara obat terikat & obat bebas dapat dipertahankan
Metode yg dipakai harus valid untuk rentang konsentrasi yg cukup besar
Kontaminasi & denaturasi protein yg akan dipakai tidak terjadi
Metode yg dipakai harus mempertimbangkan : pH, [C] ionik dr media, donan efek
Metode tsb dapat mendeteksi ikatan OP yg bersifat reversibel dan irreversibel
Hasil mencerminkan kondisi :in vivo
Kinetics of protein drug binding

Hukum : Aksi Massa
Reaksi :
The kinetics of reversible drugprotein 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)

26
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)
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)

27
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 : (see ppt)
Advantages: using direct data

Disadvantages: difficult to reach a saturated condition
[D] vs r
2. graphic method = double reciprocal plot= klotz plot
Advantages: data bias

Disadvantages: non-linier
1/[D] vs 1/r
3. scatchard plot

r/[D] = nka - rka
r vs r/[D]
Advantages: can be used for multiple binding sites non linier
Disadvantages: variability >
28
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
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

29
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
9 A drug that bind to blood component remains confined to blood have small volume of
distribution.
9 Drug that show extra-vascular tissue binding have large volume of distribution .
9 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

SIMILAR , amount of drug in plasma
Amount of drug in extravascular tissue
= Vd . C
= Vp . S
= 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)
Dividing both side by C in above equation
The fraction of unbound drug in plasma (fu)
fu = conc. of unbound drug in plasma
total plasma drug concentration
= Cu
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

30
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

31

Topic 5 : Pharmacokinetic Linier and Non Linier

Objectives:
To understand the schemes and differential equations associated with nonlinear pharmacokinetic
models
To understand the effect of parallel pathways
To estimate the parameters Km and Vm
To design appropriate dosage regimen for drugs with nonlinear elimination
introduction
what is meant by non-linear pharmacokinetics?
when the dose of a drug is increased,
we expect that the concentration at steady state will increase proportionately,
i.e. if the dose rate is increased or decreased say two-fold, the plasma drug concentration will
also increase or decrease two-fold.
However, for some drugs, the plasma drug concentration changes either more or less than
would be expected from a change in dose rate.
This is known as non-linear pharmacokinetic behaviour and can cause problems when adjusting
doses.
what causes non-linear pharmacokinetic behaviour?
it was shown that the steady state blood concentration (Css) is a function of both the dose and the
clearance of the drug.
Differentiation between Linear and Nonlinear Kinetics.
For these drugs (drugs with nonlinear kinetics or dose-dependent kinetics), the kinetic
parameters, such as clearance, volume of distribution, and half life, may vary depending on the
administered dose.
The pharmacokinetic parameters of most drugs are not expected to change when different
doses are administered or when the drug is given through different routes of administration or
as single or multiple doses.
The kinetics (e.g. clearance and volume of distribution) of these drugs are said to be linear or
dose-independent, and this is a characteristic of first-order kinetics.
The term linear simply means that if the dose is increased, the plasma concentration or area
under the plasma concentration-time curve (AUQ will be increased proportionally
However, for some drugs, this may not be valid.
For example, when the dose of phenytoin is increased by 50 percent in a patient from 300
mg/day to 450 mg/day, the average steady state concentration may increase by as much as ten
fold.
This dramatic increase in the concentration is due to the nonlinear pharmacokinetics of
phenytoin.
This is because one or more of the kinetic processes of the drug (absorption, distribution,
and/or elimination) may be via a process other than simple first-order kinetics. For these drugs,
the relationship between the AUC or CSS and dose is not linear
Additionally, different doses of these drugs may not result in parallel plasma concentrationtime courses expected for drugs with linear pharmacokinetics.
32
For example, for drugs with nonlinear metabolism, the initial decline in the plasma
concentrations may be slower at higher doses, compared with that after the administration of
the lower doses
This means that the rate of elimination is not directly proportional to the plasma concentration
for these drugs.
Sources of Nonlinearity.
As mentioned above, nonlinearity may be at different kinetic levels of absorption,
distribution, and/or elimination.
For distribution, plasma protein binding of disopyramide is saturable at therapeutic
concentrations, resulting in an increase in the volume of distribution with an increase in dose
of the drug
As for nonlinearity in renal excretion, it has been shown that the antibacterial agent
dicloxacillin has saturable active secretion in the kidneys, resulting in a decrease in renal
clearance with an increase in dose
For metabolism, both phenytoin and ethanol have saturable metabolism which means an
increase in the dose would result in a decrease in hepatic clearance and a more than
proportionate increase in the drug AUC.
Here, nonlinearity in the metabolism, which is one of the most common sources of
nonlinearity, will be discussed.
Capacity-limited metabolism is also called saturable metabolism
Michaelis-Menten kinetics, or mixed-order kinetics.
The process of enzymatic metabolism of drugs may be explained by the relationship depicted
First, the drug interacts with the enzyme to produce a drug-enzyme intermediate.
Then, the intermediate complex is further processed to produce a metabolite and release the
enzyme.
The released enzyme is recycled back to react with more drug molecules
According to the principles of Michaelis-Menten kinetics, the rate of drug metabolism (v)
changes as a function of drug concentration as demonstrated.
Based on this relationship, at very low drug concentrations, the concentration of available
enzymes is much larger than the number of drug molecules.
Therefore, when the concentration of the drug is increased, the rate of metabolism is
increased almost proportionally (linearly).
However, after certain points, as the concentration increases the rate of metabolism increases
less than proportional.
The other extreme occurs when the concentration of the drug is very high relative to the
concentration of available enzyme molecules.
Under this condition, all of the enzymes are saturated with the drug molecules, and when the
concentration is increased further, there will be no change in the rate of metabolism of the drug
In other words, the maximum rate of metabolism (V^sub max^) has been achieved

33
Proses non-linier pada tahap ADME

Absorpsi:
* transpor dalam dinding usus --- jenuh (riboflavin)
* tidak larut (griseofulvin)
* saturasi :fist past effect (salisilamid, propanolol)
* perubahan motilitas --- perubahan efek farmakologi (metoklopramida)
* kejenuhan peruraian di lambung (penicilin)
Distribusi :
* saturasi ikatan OP (salisilat)
* kejenuhan transpor (metotreksat)
Metabolisme / non renal:
* saturasi enzaim/keterbatasan ko-faktor (fenitoin,
asam salisilat)
* induksi enzim (karbamazepin)
* hepatotoksik (parasetamol)
* perubahan aliran darah hepatik (propanolol)
* penghambat metabolit (diazepam)
Ekskresi / renal:
* sekresi aktif (penisilin G)
* reabsorpsi aktif ( asam askorbat)
* perubahan pH urin, kejenuhan ikatan OP (asam salisilat)
* efek nefrotoksik (aminoglikosida)
* efek diuretik (teofilin)
Karakteristik atau fenomena kinetika non-linier
Eliminasi obat ~ non linier ~ tidak mengikuti order satu
T eliminasi > bila dosis ditingkatkan
AUC tidak sebanding dg dosis
Eliminasi fipengaruhi obat yg lain yg memerlukan enzim/carrier yg sama
Komposisi metabolit dipengaruhi oleh dosis
Kesulitan FNL : memprakirakan konsentrasi obat atas dasar dosis yg kecil
Obat-obat yg mengalami proses metabolisme terbatas/penjenuhan
Salisilat -----konjugasi glisin
Salisilamid ---konjugasi sulfat
Asam p-aminobenzoat ----asetilasi
Fenitoin ---eliminasi
Contoh proses yg dapat jenuh :
Biotransformasi
Sekresi tubular aktif ginjal
Studi FNL
Tujuan : untuk menentukan suatu obat mengikuti kinetika non linier
Cara :
(*) obat iberikan pada berbagai tingkat dosis
(*) dibuat suatu kurva konsentrasi pbat dalam plasma vs waktu untuk tiap dosis
(*) slop sejajar atau tidak

34
Eliminasi non linier

Kinetika Michaelis Menten
Laju eliminasi =
-dC/dt = {(Vm x Cp)/(Km + Cp)}
dimana :
Vm = laju eliminasi maksimum
Km = tetapan Michaelis Menten
Jika Cp << Km --- eliminasi order satu
Jika Cp >> Km --- eliminasi order nol
Nonlinear Processes
Lower concentration > first order
Higher concentration > zero order
Concentration or dose dependent kinetics
Enzyme reaction associated with metabolism may be saturable
Enzyme reaction may have a maximum rate limited by substrate
Basic enzyme kinetics have application to parmacokinetics
Michaelis-Menten Kinetics
Rate of Elimination = VmCp

Km+Cp
where Vm is the maximum rate of metabolism and Km is Michaelis constant, the concentration
(or amount) of drug at which the rate is maximum
Equation at Low Concentration
Km > Cp
Km + Cp Km
Therefore dCp/dt =- VmCp /Km =- k'Cp
pseudo first order elimination
Equation at High Concentration
Cp > Km
Km + Cp Cp
Therefore dCp / dt = - VmCp/Cp =- Vm
zero order elimination

35
High Dose - Concentration

Slope constant on linear graph == zero order
Slope approaches -Vm
Low Dose - Concentration
Slope constant on semi-log graph == first order
Slope approaches -Vm/Km
Effect of MM Kinetics on t1/2
t1/2 larger as concentration increases; i.e. slower elimination
Dc /dt =-kel x C =- Vm x C/Km+ C

since kel = 0.693/t1/2
0.693 / t1/2 = Vm / Km+ C
t1/2 = 0.693 x (Km+ C)/Vm
Persamaan
{Co Ct/t} = {Vm-{(Km/t) x ln(Co/Ct)}
t = {1/Vm x (Co/Ct)} + (Km x ln(Co/Ct)}

{Do Dt/t} = {Vm-{(Km/t) x ln(Do/Dt)}
t = {1/Vm x (Do/Dt)} + (Km x ln(Do/Dt)}
Hubungan Cp dan Vm terhadap waktu dalam penentuan dosis

D0 = 400 mg --------Dt = 20 mg
Vm = 100 mg/jam ---- t1 = 4,93 jam
Vm = 200 mg/jam ---- t2 = 2,46 jam
(Vm : tinggi --- Km : konstan---t eliminasi : turun)
D0 = 400 mg --------Dt = 20 mg
Km = 38 mg/jam ---- t1 = 2,46 jam
Km = 76 mg/jam ---- t2 = 3,03 jam
(Km : tinggi --- Vm : konstan---t eliminasi : naik)
Metode penentuan Km dan Vm pada kondisi jenuh
1. Metode A
Css = {(Vm x Css) / R} + (1/Vm)
2. Metode B
R = {-Km x (R/Css)} + (Vm)
3. Metode C
R = { (Vm x Css)/(Km+ Css)}
4. Metode D
R1 = { (Vm x C1)/(Km+ C1)}
R2 = { (Vm x C2)/(Km+ C12}

36
Metode penentuan Km dan Vm pada kondisi tanpa penjenuhan

* Metode 1
1/V = { (Km/Vm) x 1/C)} + (1/Vm)
* Metode 2
C/V = { (1/Vm) x C)} + (Km/Vm)
* Metode 3
V = - {Kmx (V/C)} + Km/Vm
Farmakokinetika yang disebabkan oleh ikatan OP :
a. t eliminasi ---- lebih panjang
b. filtrasi glomerulus
c. bila Cp ----- fb
Saturation of elimination mechanisms causes a change in intrinsic clearance

Drug metabolism
The metabolism of drugs is carried out by a variety of enzymes such as cytochromeP450 and Nacetyltransferase. The dependence of the rate of an enzyme reaction on substrate concentration
is given by the Michaelis-Menten equation
At high drug concentrations, the maximal rate of metabolism is reached and cannot be
exceeded.
Under these conditions, a constant amount of drug is eliminated per unit time no matter how
much drug is in the body.
Zero order kinetics then apply rather than the usual first order kinetics where a constant
proportion of the drug in the body is eliminated per unit time.
Some examples of drugs which exhibit non-linear kinetic behaviour are phenytoin, ethanol,
salicylate and, in some individuals, theophylline.
Example - Phenytoin
Average Km 4 mg/L (1 - 15 mg/L)
Average Vm = 500 mg/day (100 - 1000 mg/day)
Therapeutic window 10 - 20 mg/L (total Cp)
Overdose possible if dose adjustment is not appropriate
Half-life at low doses 12 hr, maybe greater than 24 hr at higher doses
From 25 to 23 mg/L in 24 hours (cf. 25 > 12.5 > 6 mg/L when t1/2 is 12 hr)
Phenytoin:
Phenytoin exhibits marked saturation of metabolism at concentrations in the therapeutic
range (10-20 mg/L)
Consequently, small increases in dose result in large increases in total and unbound
steady state drug concentration.
As an example, for a patient with typical Km of 5 mg/L (total drug) and Vmax of 450
mg/day, steady state concentrations at doses of 300, 360 and 400 mg/day would be 10.0,
20.0 and 40.0 mg/L respectively (Fig. 2).
Thus, small dosage adjustments are required to achieve phenytoin concentrations in the
therapeutic range of 10-20 mg/L.

37
A second consequence is that, because clearance decreases, apparent half-life increases from about
12 hours at low phenytoin concentrations to as long as a week or more at high concentrations.
This means that
i. the time to reach steady state can be as long as 1-3 weeks at phenytoin concentrations near the
top of the therapeutic range
ii. in the therapeutic range, the phenytoin concentration fluctuates little over a 24 hour period
allowing once daily dosing and sampling for drug concentration monitoring at any time between
doses
iii. if dosing is stopped with concentrations in the toxic range, phenytoin concentration initially falls
very slowly and there may be little change over a number of days.
Alcohol:
Alcohol is an interesting example of saturable metabolism.
The Km for alcohol is about 0.01 g% (100 mg/L) so that concentrations in the range of
pharmacological effect are well above the Km.
The Vmax for ethanol metabolism is about 10 g/hour (12.8 mL/hour) and it can be calculated
(see legend to Fig. 2) that at the common legal driving limit of 0.05 g%, the rate of alcohol
metabolism per hour is 8.3 g/hour.
This amount of alcohol is contained in 530 mL light beer, 236 mL standard beer, 88 mL wine or
27 mL spirit.
Higher rates of ingestion will result in further accumulation.
Renal excretion
In Article 7 (`Clearance of drugs by the kidneys' Aust Prescr 1992;15:16-9), it was shown that
renal drug clearance is the sum of filtration clearance plus secretion clearance minus
reabsorption.
Clearance by glomerular filtration is a passive process which is not saturable, but secretion
involves saturable drug binding to a carrier.
Even when secretion is saturated, filtration continues to increase linearly with plasma drug
concentration.
The extent to which saturation of renal secretion results in non-linear pharmacokinetics depends
on the relative importance of secretion and filtration in the drug's elimination.
Because of the baseline of filtration clearance, saturation of renal secretion does not usually
cause clinically important problems.
Saturation of first pass metabolism causing an increase in bioavailability
After oral administration, the drug-metabolising enzymes in the liver are exposed to relatively
high drug concentrations in the portal blood.
For drugs with high hepatic extraction ratios, e.g. alprenolol, an increased dose can result in
saturation of the metabolising enzymes and an increase in bioavailability (F).
Steady state drug concentration then increases more than proportionately with dose (equation
3). Other drugs with saturable first pass metabolism are tropisetron and paroxetine.

38
Saturation of protein binding sites causing a change in fraction of drug unbound In plasma
In a few cases (e.g. salicylate, phenylbutazone, diflunisal), therapeutic drug concentrations are
high enough to start to saturate albumin binding sites so that unbound protein concentration
decreases and fu increases while total drug concentration increases less than proportionately
with increases in dose
This occurs more commonly for drugs such as disopyramide which bind to a1 acid
glycoprotein because of the lower concentration of binding protein.

39

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BAHAN AJAR

MATA KULIAH FARMAKOKINETIKA

Universitas Katolik Widya Mandala

Rencana Program dan Kegiatan Pembelajaran Semester (RPKPS)

Shargel & Yu (1999)

Rowland & Tozer (1989)

Drug protein binding

Rowland & Tozer (1989)

Kinetics of drug protein binding

Non Linear pharmacokinetics

Hepatic and biliary metabolism (I)

Drs. Kuncoro Foe, Ph.D

Rowland & Tozer (1989)

Hepatic and biliary metabolism (II)

Drs. Kuncoro Foe, Ph.D

Shargel & Yu (1999)

Hepatic and biliary metabolism (III)

Drs. Kuncoro Foe, Ph.D

Shargel & Yu (1999)

Renal excretion (I)

Drs. Kuncoro Foe, Ph.D

Shargel & Yu (1999)

Renal excretion (II)

Drs. Kuncoro Foe, Ph.D

Dosen 1 : MM Farida Lanawati Darsono, S.Si.,M.Sc

Nilai UTS dan UAS @ : 100

References (for all topic)

BAHAN AJAR : FARMAKOKINETIKA

Topic 1 : Introduction and Routes of Administration

Do not cited this article without permittion from Ms. Farida

rute pemberian obat

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BAHAN AJAR : FARMAKOKINETIKA

Topic 2 : Drug Distribution

pattern 4 is the most common being a combination of patterns 1,2 and 3

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The important factors in dtermining the rate of drug diffusion are :

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10 without permittion from Ms. Farida

Vd equal or higher than total body water

Diffusion to intracelullar fluid . Vd equal to total body water.

Key factor in the onset of drug action-Body Water Compartments

Tissue Permeability of the Drugs depend upon:

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Blood Cerebrospinal Fluid Barrier:

Tissue protein binding

Plasma protein binding

WHAT IS THE EFFECT OF BARRIERS TO DRUG DIFFUSION ON DRUG

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WHAT IS THE EFFECT OF PLASMA PROTEIN BINDING ON DRUG DISTRIBUTION?

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BAHAN AJAR : FARMAKOKINETIKA

Topic 3 : Drug Accumulation in Lysosom

Lysosomes are vesicles produced by the Golgi aparatus.

Ion trapping: lysosomes

: [Bun] inside = [Bun] outside

: [A-] outside >[A-] inside

Weak base ---- ion trapping ------- accumulation (Vd >>>)

Accumulation of Drugs in Tissues

Intracellular Distribution-based Anticancer Drug Targeting: Exploiting a Lysosomal

propensity of drugs with optimal physicochemical properties to distribute differently in normal