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u an o, ., ., . .
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IntroductionToxicology:
a subject concerned with the study of the
living systems
Xenobiotics substances foreign to living
, . . , Normal body constituents at toxic levels
. . ,
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IntroductionParacelsus (14931541):
that is not a poison. The right dose
no observable effect and another, higher
,
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IntroductionIntoxication:
interaction between a chemical poison and
sustains life
1. Exposure to the chemicals
2. Disposition3. Toxic response
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IntroductionExposure to the chemicals:.
gastrointestinal tract.
3. Inhalation exposure via respiratory
4. Parenteral exposure by injection
. er rou es
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IntroductionDisposition:
a. Absorption The chemicals must cross cell membranes
Cell membranes composed of long-chain
phospholipids bilayer studded with andpenetrated by bands of protein
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Introductiona. Absorption
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Introductiona. Absorption
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Introductiona. Absorption Membranes are selectivel ermeable
Physicochemical characteristics of, . .
a. size/shape
.
c. structural similarity to endogenous
d. charge/polarity.
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Introductiona. Absorption Forei n com ounds ma ass across
membranes by:.
2. Passive diffusion
.
4. Facilitated diffusion
5. agocytos s p nocytos s.
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Introductiona. Absorption1. Filtration:
diffusion through pores in the membrane
Foreign compounds: small, hydrophilic, . . ,
urea
such as sodium will not pass through pores
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Introductiona. Absorption1. Filtration:
Pore sizes vary between cells and tissues,.
molecules with MW of several thousand
ma ass it2. Passive diffusion:
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Introductiona. Absorption2. Passive diffusion:
Requirement:. .across the membrane
. .soluble
. . -
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Introductiona. Absorption2. Passive diffusion:
2.1. There must be a concentration gradient
Ficks Law:
= t e sur ace areaC2 = the concentration of compound on the
outside of the membrane
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Introductiona. Absorption2. Passive diffusion:
2.1. There must be a concentration gradient
C1 = the concentration of compound on the
d = is the thickness of the membrane
= t e us on coe c ent, a constant afunction of lipophilicity, size, shape, etc.
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Introductiona. Absorption2. Passive diffusion:
2.1. There must be a concentration gradient
biological systems are dynamic the
maintained thus passive diffusion is not asaturable rocess
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Introductiona. Absorption2. Passive diffusion:
2.1. There must be a concentration gradient
the concentration on the inside of the
as a result of ionization, metabolism , andremoval b distribution into othercompartments such as via blood flow
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Introductiona. Absorption2. Passive diffusion:
2.2. The foreign compound must be lipid
Lipophilicity: the ability of a substance to
Lipid solubility: an intrinsic property of a
,denoted by the partition coefficient, KP (or
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Introductiona. Absorption2. Passive diffusion:
2.2. The foreign compound must be lipid
Clipid = concentration of compound in the lipid
Cwater= concentration of compound in thewa er p ase
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Introductiona. Absorption2. Passive diffusion:
2.2. The foreign compound must be lipid
Drugs % absorbed through
intestinal
wall
Kchloroform
Thiopental 67 100
Aniline 54 26,4
Acetanilide 43 7,6
Acetylsalicylic
acid 21 2,0Barbituricacid 5 0,008
Mannitol
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Introductiona. Absorption
2. Passive diffusion:
2.2. The foreign compound must be lipid
The larger the partition coefficient the
Although there is often a good correlation
through membranes, very lipophilic
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Introduction (AKHIR KULIAH 1)
a. Absorption
2. Passive diffusion:
2.3. The compound must be non-ionized
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Introductiona. Absorption
2. Passive diffusion:
2.3. The compound must be non-ionized
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Introductiona. Absorption
2. Passive diffusion:
2.3. The compound must be non-ionized
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Introductiona. Absorption
3. Active trans ort:
Important features:. .required
,protein carriers:
. . .actively or passively transport one molecule.
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Introductiona. Absorption
3. Active trans ort:
I3.1.2. Symports involve the transport of two
3.1.3. Antiports involve the transport of two
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Introductiona. Absorption
3. Active trans ort:
3.2. Metabolic energy is necessary to operate
Active transport requires a source of energy,
carrier protein, or the co-transport of ionssuch as Na+ or H+ down their
electrochemical gradients
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Introductiona. Absorption
3. Active trans ort:
3.3. Transport occurs against a concentration
3.4. The process may be inhibited by metabolic
3.5. The process may be saturated at high
3.6. Substrates may compete for uptake.
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Introductiona. Absorption
4. Facilitated diffusion:
Important features:. .molecule
. .competitively inhibited.
. .a concentration gradient
. . ere s no requ remen or me a o c
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Introductiona. Absorption
5. Pha oc tosis/ inoc tosis:
forms of endocytosis (a process of cellular
folds inward to bring substances into the
cell involve the invagination of the membrane to
enclose a article or dro let res ectivel
The process requires metabolic energy and
molecules, such as ions, in the surroundingmedium. Budhijanto, 2009
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Introductiona. Absorption
5. Pha oc tosis/ inoc tosis:
The result is the production of a vesicle
become a secondary lysosome in which the
enz mes ma di est the macromolecule In some cases a particular part of the
lasma membrane with s ecific rece tors
binds the macromolecule and theninvaginates
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Introductiona. Absorption
a.1. Absor tion throu h skin:
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Introductiona. Absorption
a.1. Absor tion throu h skin:
by passive diffusion mainly through the.
Compounds are generally lipophilic, e.g.
, Lipophilicity is not always a prerequisite for
necessarily a good correlation
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Introductiona. Absorption
a.2. Absor tion throu h lun s:
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Introductiona. Absorption
a.2. Absor tion throu h lun s:
Usually rapid and efficient
The solubility in the blood is a major factor in.
For compounds with low solubility the rate of
dependent on blood flow (perfusion limited)
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Introductiona. Absorption
a.2. Absor tion throu h lun s:
For compounds with high solubility in the,
blood will be mainly dependent on
res iration rate ventilation limiteda.3. Absorption through gastrointestinal tract:
gastrointestinal tract varies throughout its
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Introductiona. Absorption
a.3. Absor tion throu h astrointestinal tract:
the lining of the mouth (buccal cavity), the,
alkaline in some other species, e.g rat.
,certain other mammals.
, .
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Introductiona. Absorption
a.3. Absor tion throu h astrointestinal tract:
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Introductiona. Absorption
a.3. Absor tion throu h astrointestinal tract:
Lipid soluble, nonionized compounds may
Ionizable substances will generally only be
non-ionized at the pH of the particular siteand are also li id soluble
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Introductiona. Absorption
a.3. Absor tion throu h astrointestinal tract:
e.g. pKa of benzoic acid = 4,202; pKa of aniline= ,
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Introductiona. Absorption
a.3. Absor tion throu h astrointestinal tract:
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Introductiona. Absorption
a.3. Absor tion throu h astrointestinal tract:
The absorption from the gastrointestinal tract
compounds so absorbed are transported
directl to the liver. Extensive metabolism inthe liver may alter the structure of thecompound, making it more or less toxic.
Little of the parent compound reaches thesystemic circulation in these circumstances.
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Introductiona. Absorption
a.3. Absor tion throu h astrointestinal tract:
It may lead to different toxicity after.
.
Through bloodstream
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