DISTRIBUTION AND EXCRETION OF KLORAMFENIKOL EYE DROPS

Cindy Yosunarto, Dedek Suwanda, Egy Pebrina Sembiring, Feti Fera, Resky
Oktaviani, Reza Ardian, Tuti Nanda Yuliana, Yasrina

Pharmacy Study Program Faculty of Mathematics and Natural Sciences

Sriwijaya University Indralaya
email: [email protected]

ABSTRACT

In the process of drug pharmacokinetics after a drug undergoing phase

absorption, distribution, biotransformation, and the drug is finally experiencing a phase
of excretion. Excretion is the displacement of the systemic circulation of drugs heading
to the organs of excretion. Experienced drug excretion aims to detoxify drugs, because
it is known that the drug is considered a poison/foreign substances by the body.
Chloramphenicol works by inhibiting protein synthesis germs. The drug is bound to the
Ribosome sub-unit 9s and inhibits the enzyme peptidil transferase so the peptide bonds
are not formed in the process of protein synthesis germs. Chloramphenicol are
bacteriostatic. At high concentrations of chloramphenicol sometimes are bakterisid
against particular germs. This trial will be observed on distribution and excretion of
chloramphenicol eye drops

Keyterm : Chloramphenicol, distribution, excretion, eye drops.

1. INTRODUCTION required drug concentration in the place
of absorption and sustaining it for
Ophthalmic drug forms have
appropriately long time, which in turn
been one of the most important and
contributes to smaller application
widely developed areas of
frequency(1).
pharmaceutical technology for dozens
of years. The main reason of One of the first modifications to
continuingly strong interest of scientists conventional forms of ophthalmic drugs
in these drug forms is the problem of a was introducing polymers to
low bioavailability of medicinal formulation, which enabled longer
substance after the application to the contact time of active ingredient and the
eyeball. It is caused by, amongst other corneal surface, thus increasing its
reasons, the complicated anatomical bioavailability. Next possibility to
structure of the eye, small absorptive modify the ophthalmic forms active
surface and low transparency of the ingredients’ bioavailability involved
cornea, lipophilicity of corneal introducing excipients to formulation,
epithelium, metabolism, enzymolysis, which enhanced drugs’ penetration into
bonding of the drug with proteins the eyeball. These excipients included
contained in tear fluid, and defence chelating agents, surfactants, and
mechanisms, that is, tear formation, cyclodextrins, which, along with active
blinking, and flow of the substance ingredients, form inclusion complexes.
through nasolacrimal duct (1). This increases solubility, permeability,
and bioavailability of poorly soluble
Low capacity of conjunctival sac,
drugs (1).
that is, approximately 30 L without
blinking [4], and the aforementioned The newer drug forms, on which
defence mechanisms cause decrease in in recent years research has been
drug concentration in the place of conducted in order to achieve a
application and shorten the time during controlled release of drug to eyeball
which the active ingredient stays in the tissues, include multicompartment
place of absorption. The primary carrier systems, inserts, collagen
purpose for the development of shields, contact lenses, and the so-called
ophthalmic drug forms is to achieve the in situ gels [1–3, 5]. The advantages of
using these new drug forms of Eye drops are usually used on the
controlled release are, among others, eyes for the purpose of local effects on
increasing bioavailability of substance treatment of the surface of the eye or on
through extending the time of its contact the inside, where the most often used is
with cornea—which can be achieved by a solution in water. Because of eye
effective adhesion to the corneal capacity to withstand or keep the fluid
surface, the possibility of targeted limited, in general eye medication is
therapy preventing the loss of drug to given on a small volume. Larger volume
other tissues, ensuring patient’s comfort of liquid preparation can be used to
when applying the drug form and during refresh or wash eyes(4).
the whole therapy, and increasing
The normal volume of tears in
resistance to eye defence mechanisms,
the eye is 7micro liter. Where the eyes
like tearing (2).
are not blinking can contain at most
Eye drops are accessible in the 30micro liter liquid, while the eyes are
forms of water and oil solutions, blinking only can save 10 micro liter
emulsions, or suspensions of one or fluids. Excess fluid, both from normal
more active ingredients, which may production or added from the outside,
contain preservatives if stored in quickly flowed into the eye. The size of
multiuse packaging. These forms are each drop which is incorporated into a
sterile and isotonic. The optimum pH 50-drug solution usually micro liter
for eye drops equals that of tear fluid (based on 20 drops / ml), so the droplet
and is about 7.4. In deciding whether to inserted will mostly be lost. Ideal
buffer the drug in this form, one should volume of drug solution to be used,
take into account the stability of active based on the capacity of the eye ie 5-10
ingredient and the tissue tolerance to the micro liter. Because the dose of
preparation. If the pH value gets outside microliter from eye dropper is usually
the range of 4–8 which is tolerated by absent or not used by the patient, the
eye, the patient may feel discomfort, loss of that drug inserted a standard eye
there may be irritation, and the drug dropper is common. If desired therapy
bioavailability can decrease because of with a few drops, it is recommended to
increased tearing (3). repeat every 5 minutes. This matter
allows the buildup of drugs in the networks in the water. Examples of such
corner, while losing through drainage polymers include polyvinyl alcohol,
small. Sometimes the use of a solution poloxamers, hyaluronic acid,
for the eyes with greater concentrations carbomers, and polysaccharides, that is,
of the drug can be replaced for cellulose derivatives, gellan gum, and
treatment with repeated droplets of the xanthan gum. The aforementioned
solution more dilute(5) . carbomer is used in liquid and semisolid
formulations as a suspending substance
The buffer may be used in an eye
or a substance which increases
solution because of one or all of these
viscosity, whereas hyaluronic acid is
the following reasons to reduce the
used as a polymer, forming
discomfort of the patient to guarantee
biodegradable and biocompatible
stability of the drug, and to supervise
matrix, which enables extending time
the therapeutic activity of medicinal
periods of drug release (6).
substances.
The research has proved that
Tears have a normal pH of 7.4
maximum increase of penetration
and have a buffer ability. The use of a
through the cornea by a solution in the
solution containing eye medication
form of eye drops takes place when the
stimulates the flow of tears trying to
viscosity falls into the range of 15 to
neutralize any excess hydrogen or
150 mPas. An example of “extreme”
hydroxyl ions imposed on eyes together
use of substances increasing viscosity is
solution (5)
forming gels, which would enable
Extending the time period of reducing the frequency of drug
contact with cornea and improving application to once daily. It has been
bioavailability of substances may be proved that synthetic
obtained by increasing formulation’s polyoxyethylene-polyoxypropylene
viscosity. Substances which have such block copolymer (poloxamer 407) is
effect include hydrophilic polymers of suitable for use as a carrier in
high molecular weight which do not ophthalmic formulation with
diffuse through biological membranes pilocarpine, which stimulates the active
and which form three-dimensional ingredient. The main disadvantage of
this formulation is blurring of vision, chloramphenicol degradation. This drug
which negatively affects its is very unstable in an alkaline
acceptability among patients (6). atmosphere, andhis reactions appear to
be catalyzed by both acid and specific
Chloramphenicol is one of the
bases(7). Chloramphenicol degradation
most chemically known antibiotics
through dehalogenation is not a part of
stable in all usage. Chloramphenicol has
the role in the picture of total
excellent stability at room temperature
degradation, at least below pH 7(7).
and pH range 2 to 7, its maximum
stability is achieved at pH 6. At The degradation rate depends
temperature 25°C and pH 6, has a linearly on the concentration of buffer,
half-life of almost 3 years. The cause buffer species acting as common acids
the main occurrence of chloramphenicol and common bases. The rate of
degradation in aqueous media is the hydrolysis of chloramphenicol is not
hydrolytic solutionon the amide circle. depending on ionic strength, and
The reaction rate lasted under the first unaffected by the concentration of
order and was not depending on the dihydrogen phosphate ions,thus its
ionic strength of the media (7). catalysis activity is thought to be
derived from the action of the
Ongoing hydrolysis of
monohydrogen ionphosphate as general
chloramphenicol catalyzed common
base catalysis(7).
acids / common bases, but in the pH
range of 2 to 7, the reaction rate is Chloramphenicol is a
independent of pH. Species catalyzing broad-spectrum antibiotic that was
is a common acid or a common base derived from the bacterium
contained in a buffer solution used; Streptomyces venezuelae and is now
particularly in monohydrogen phosphate produced synthetically.
ions, undissociated acetic acid, and Chloramphenicol is effective against a
monohydrogen acid and dihydrogen wide variety of microorganisms, but due
citrate ions can catalyze the degradation to serious side-effects (e.g., damage to
process. In under pH 2, hydrolysis of the bone marrow, including aplastic
hydrogen ion-specific catalyzed plays a anemia) in humans, it is usually
major role on occurrence of reserved for the treatment of serious and
life-threatening infections (e.g., typhoid major route of elimination of
fever). Chloramphenicol is chloramphenicol is hepatic metabolism
bacteriostatic but may be bactericidal in to the inactive glucuronide. This
high concentrations or when used metabolite, as well as chloramphenicol
against highly susceptible organisms. itself, is excreted in the urine by
Chloramphenicol stops bacterial growth filtration and secretion. Over a 24 hour
by binding to the bacterial ribosome period, 75% to 90% of an orally
(blocking peptidyl transferase and administered dose is so excreted; about
inhibiting protein synthesis (8). 5% to 10% is in the biologically active
form(8).
Chloramphenicol is a
semisynthetic,broad-spectrum antibiotic Chloramphenicol inhibits protein
derived from Streptomyces venequelae synthesis in bacteria and, to a lesser
with primarily bacteriostatic activity. extent, in eukaryotic cells. The drug
Chloramphenicol diffuses through the readily penetrates into bacterial cells,
bacterial cell wall and reversibly binds probably by a process of facilitated
to the bacterial 50S ribosomal subunit. diffusion. Chloramphenicol acts
The binding interferes with peptidyl primarily by binding reversibly to the
transferase activity, thereby prevents 50 S ribosomal subunit (near the site of
transfer of amino acids to the growing action of the macrolide antibiotics and
peptide chains and blocks peptide bond clindamycin, which it inhibits
formation. As a result bacterial protein competitively). Although binding of
synthesis is blocked and impede tRNA at the codon recognition site on
bacterial cell proliferation (8). the 30 S ribosomal subunit is thus
undisturbed, the drug appears to prevent
Rapidly and completely
the binding of the amino
absorbed from gastrointestinal tract
acid-containing end of the aminoacyl
following oral administration
tRNA to the acceptor site on the 50 S
(bioavailability 80%). Well absorbed
ribosomal subunit. The interaction
following intramuscular administration
between peptidyl transferase and its
(bioavailability 70%). Intraocular and
amino acid substrate cannot occur, and
some systemic absorption also occurs
peptide bond formation is inhibited.
after topical application to the eye. The
Chloramphenicol can also inhibit 2.3.1.Preparation
mitochondrial protein synthesis in
1. The group chose 2 volunteers for
mammalian cells, perhaps because
the experiment.
mitochondrial ribosomes resemble
2. Before an ophthalmic drug, the
bacterial ribosomes (both are 70 S)
bladder is emptied and urine
more than they do the 80 S cytoplasmic
taken for control, saliva is also
ribosomes of mammalian cells.
taken for control, as well as tears
Mammalian erythropoietic cells seem to
taken for control.
be particularly sensitive to the drug(8).
3. Volunteers were given 2 drops of
2. RESEARCH METHODOLOGY chloramphenicol eye medicine.
4. Saliva and urine samples taken
2.1 Time and place
every 15 minutes for 3 hours and

This experiment was conducted tears every 30 minutes for 3

at Pharmacology Laboratory, Faculty of hours. Do urine and saliva

Mathematics and Natural Sciences, analysis.

Sriwijaya University of Palembang. The

2.3.2.Analytical Procedures
time of its implementation on 26 sept ,
2017. 1. Dissolve saliva, tears and urine
in 1ml ethanol 95%.
2. Add 3ml of water mixture and 1

2.2 Tools and Materials part KCL and 9 parts water.

3. Add 50 mg Zn powder.
The tools used are dropper 4. Heat over the water bath for 10
drops, test tube, ointment pot, test tube.. minutes
The ingredients used include 5. Pour the pour.
chloramphenicol drops 5%, ethanol 95 6. Add 1o mg of anhydrous sodium
%, KCL, aquadest, anhydrous sodium acetate and 2 drops of benzoyl
acetate, Zn powder, benzoyl chloride, chloride. Shake for 10 minutes.
FeCL3, HCL 0.1 N 7. Add 0.5 ml of fecl3 solution, if
necessary add HCL dilute
2.3. Procedure
enough to make clear solution
 and change the color of violet two hours at 48 hours early and four
red to purple. hours afterwards. Sleep does not need to
be disturbed for eye drops. The usual
3. RESULT AND DISCUSSION
treatment takes five days.
The experiment at this time Chloramphenicol is a bacteriostatic that
made an observation of the distribution has a wide spectrum of gram-negative
and excretion of chloramphenicol eye and gram-positive bacteria.
drops through urine, saliva and tears. Chloramphenicol provides antibacterial
With the aim of knowing effects by binding to bacterial
pharmacokinetics of chloramphenicol ribosomes and inhibits bacterial protein
eye drops. This experiment used two synthesis. In acute conjunctive disease,
volunteers for an experimental usually caused by staphilokoci or
administration of chloramphenicol eye streptococi in adults, and also
drops previously emptied of each Haemophilus influenzae and Moraxella
volunteer bladder aiming to see the catarrhalis. The characteristics of a
excretion of the drug which was given conjunctive infection are (bacteria or
not mixed with other compounds to be virus): the eyes look swollen and red or
identified chloramphenicol compounds pink, uncomfortable eyes are felt with a
by quantitative identification with the burning or sandy feeling (but not sharp
compound the previously treated FeCl 3 or important pain) and dirt. Eye
reagents with 95% ethanol. droppings are sticky and mokopurulent
Chloramphenicol is one of the most to bacteria and more watery than viral
chemically stable antibiotics in all infection. Bacterial conjunctivitis can
applications. Chloramphenicol itself also make eyes difficult to open in the
excellent stability at room temperature morning due to dry debris. Conjunctive
range of 3-7 ph is a good stability. infections usually begin in one eye and
then spread elsewhere. Vision is not
Chloramphenicol is indicated for
disturbed usually, but when associated
topical treatment of acute bacterial
with eye droppings, causing blurred
conjunctive infections in adults, elderly,
vision, and there are particles that look
and children 2 years or older. Used as
motionless. There is no photophobia.
many as one drop in the infected eye for
 Drugs that enter the body will process of drug absorption is the
undergo pharmacokinetics process. transfer of drugs from one place to
Basically pharmacokinetics is all the another, from the gastrointestinal tract
process that the body does to drugs in to the blood vessels, to the penetration
the form of absorption, distribution, of the membrane. The main factors
metabolism (biotransformation), and affecting absorption after oral
excretion. Our body can be regarded as administration of the drug, there are 3
a large room, consisting of several factors, namely: physiological factors,
compartments separated by cell physico-chemical factors, and
membranes. While the process of formulation factors. The medicine in the
absorption, distribution and excretion of dosage form will be released into drug
drugs from within the body in essence particles in the body fluids to be
take place with the same mechanism, dissolved and the drug is in the form of
because this process depends on the a solution that can be degraded or
trajectory of the drug through the absorbed into the liver and can be
trajectory. The cell membrane consists excreted (if polar drugs, either directly
of a layer of lipoprotein (fat and protein) excreted) or into the central
containing many small pores, filled with compartment bound form or free form,
water. Membranes can be penetrated achieving dynamic equilibrium) then
easily by certain substances, and the drugs are distributed and only the
difficult to pass through other over-the-counter drugs reach the
substances, it is called semi permeable. peripheral tissues that cause
Lipofil substances (like fat) that are pharmacological effects. The drug after
easy to laryt in fat and without electric absorption will spread through the blood
charge generally run more smoothly circulation throughout the body. In the
than hydrophilic substances with charge circulation, most drugs are distributed
(ion). through the membrane of the body in a
way that is relatively easier and faster
Drugs consumed by living
than the elimination or expenditure of
things will essentially undergo the
drugs. Distribution is the process of a
process of adsorption, distribution,
drug that reversibly leaves the
metabolism and elimination. The
bloodstream and enters the interstitium
(extracellular fluid) or to the tissue cells. Within 24 hours 75-90% of oral doses
Drug deliveries from plasma to are excreted in the form of metabolites
interstinum depend primarily on blood and 5-10% in the original form. While
flow, capillary permeability, the degree on the sempel urine is known to have
of ionic bonding of the drug to plasma chloramphenicol content of each time, it
or tissue proteins and the is proved by positive results reacted
hydrophobicity of the drug. between sempel with FeCl3 which form
a red color to purple that previously
Volunteers who have been given
sempel diluted first with 95% ethanol
eye drops previously performed bladder
and precipitated with KCL and Na
emptying aimed at the excretion of
acetate and benzoyl chloride and reacted
chloramphenicol eye drops can be
with FeCl3 forming the compound into
identified in the body. Urine, saliva and
red to purple, from the above data it can
tears taken before and after
be concluded that chloramphenicol is
chloramphenicol eye drops, results
excreted through urine by means of
obtained before chloramphenicol eye
glomerular filtration and secretion.
drops, urine and tear drops showed
Within 24 hours 75-90% of oral doses
negative results reacted with FeCl3
are excreted in the form of metabolites
reagents did not show results as red to
and 5-10% in the original form.
purple as no occurrence of complexing
between chloramphenicol and FeCl3. 4. CONCLUSION
While on the sempel that has been given
Drugs that enter the body will
chloramphenicol eye drops taken every
undergo pharmacokinetics process.
saliva and urine taken 15 minutes once
Basically pharmacokinetics is all the
for 3 hours while for tears taken 30
process that the body does to drugs in
minutes for 3 hours. In tamp and saliva
the form of absorption, distribution,
sempel produce negative data every seal
metabolism (biotransformation), and
because sempel does not form a
excretion. Chloramphenicol is excreted
complex red to purple bond with FeCl3,
through the urine after going through
this is due to the excretion of
filtration processes in the glomerulus
chloramphenicol through urine by
and secretion processes. Within 24
glomerular filtration and secretion.
hours 75-90% of oral doses are excreted
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157-163, 540-551.
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