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Chapter 3
Transportation and
Transformation of
Xenobiotics
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•[exposure]
•skin
•[absorption]
•[distribution]
blood
•lung
•Albumin binding
•[exposure]
•(hazard)
•Organ,
•liver
•dissociating
•tissue
•digestive
tract
•(storage)
•kidney
• feces
•Target
organ
•bile
•lung
•Secretion ligand
•[excretion]
•urine •expired gas •Milk,sweat
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Basic Conceptions
• Disposition: Absorption, Distribution, metabolism,
Excretion (ADME)
• Biotransportation: Absorption, Distribution,
Excretion
• Biotransformation: Metabolism
• Elimination: Metabolism, Excretion
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Basic Conceptions
• Toxicokinetics: ADME
• Toxicodynamics: Interaction, Effects
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Section 1
Absorption
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组织间隙液体
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Cell Membranes
• A phospholipid bilayer with polar head
groups on both surfaces.
• Proteins or glycoproteins are inserted in
or across the bilayer.
• The fluid character of membranes is
determined largely by the structure and
relative abundance of unsaturated fatty
acids.
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Transport
• Passive transport: simple diffusion;
filtration; facilitated diffusion
• Active transport:
• Cytosis:endocytosis;
exocytosis( phagocytosis and pinocytosis )
• Energy needed?
• Carrier molecule needed?
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Transport
1. Passive diffusion. Diffusion occurs through the
lipid membrane.
2. Filtration. Diffusion occurs through aqueous pores.
3. Special transport. Transport is aided by a carrier
molecule, which act as a “ferryboat.”
4. Endocytosis. Transport takes the form of
pinocytosis for liquids and phagocytosis for solids.
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Passive diffussion
Rate of diffusion 
D  S a  Pc
(CH  CL )
d
D is the diffusion coefficient, is primarily dependent on
solubility of the toxicant in the membrane and its
molecular weight and molecular conformation.
Sa is the surface area of the membrane,
Pc is the partition coefficient, the relative solubility of the
compound in lipid and water,
d is the membrane thickness,
CH and CL are the concentrations at both sides of the
membrane (high and low, respectively).
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Absorption
• Absorption: Transfer of a chemical from
the site of exposure into the systemic
circulation by cross body membranes.
• The main sites of absorption are the GI
tract, lung and skin, but there are other
ways of administration including
enteral(肠内的)and parenteral routes.
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Factors Altering the GI
Absorption of Toxicants
•
•
•
•
•
pH of the GI 影响酸碱的解离和穿膜扩散
Residency time of compounds
Physical properties of chemicals 亲水性和亲脂性
First-pass effect
有些毒物在进入体循环之前首先在胃肠道、肠黏膜细胞和肝脏灭活代谢一部分（主要在肝脏），导致进入体循
环的实际毒物量减少，这种现象称首过消除(first-pass elimination)或第一关卡效应,或首关效应（first-pass
effect）。
• Food: ion, milk
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Factors Altering the GI
Absorption of Toxicants
Enterohepatic circulation
• The resident bacterial population can metabolize drugs in the GIT.
• If the toxicant survive these microbial and chemical reactions in the
stomach and small intestine, it is absorbed in the GIT and carried by the
hepatic portal vein to the liver, which is the major site of metabolism.
• this activity in the liver can result in detoxification and/or bioactivation.
Some drugs and toxicant that are conjugated (e.g., glucuronidation糖脂
化 ) in the liver are excreted via the biliary system back into the GIT.
• Once secreted in bile by active transport and excreted from the bile duct
into the small intestine, this conjugated toxicant can be subjected to
microbial beta-glucuronidase activity that can result in regeneration of
the parent toxicant that is more lipophilic than the conjugate.
• The toxicant can now be reabsorbed by the GIT, prolonging the
presence of the drug or toxicant in the systemic circulation. This is
called enterohepatic circulation。
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Factors altering the lung
absorption of toxicants
•
•
•
•
•
Gases and vapors
Blood-to-gas partition-coefficient
Aerosols and particles
Solubility （不同的溶解度在不同部位吸收）
Size: 2-5μmainly deposited in the tracheo
bronchium
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Factors Altering the Skin
Absorption of Toxicants
•
•
•
•
•
Molecular weight
Lipid/water solubility
Condition of the skin
Cutaneous blood flow
Solvents
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Section 2
Distribution and Excretion
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Distribution
• Distribution: Blood to target organ
• Affecting factors: volume of blood flow ;
Tissue affinity of xenobiotics
• Distribution and Redistribution:
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Distribution
• Plasma water
• Extracellular water
• Intracellular water
• Redistribution: organ affinity
• Perfusion of tissues
• Tissue binding
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Usually after a toxicant or drug is absorbed it can be distributed into various physiologic fluid compartments.
Table 6.5 Volume of Distribution into Physiological Fluid Compartments
Compartment
Volume of Distribution in L/kg Body Weight (Ls/70 kg Body weight)
Plasma
0.05(3.5 L)
Interstitial fluid
0.18(12.6 L)
Extracellular fluid
0.23(16.1 L)
Intracellular fluid
0.35(24.5 L)
Total body water
0.55(39 L)
Storage of Toxicant in Tissues
•
•
•
•
•
Plasma protein
Liver and kidney
Fat
Bone
Barrier: blood-brain, placenta
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Excretion
•
•
•
•
•
•
•
Urinary excretion
Fecal excretion
Biliary excretion
Intestinal excretion
Exhalation
Milk
Sweat and saliva
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TOXICOKINETICS
The apparent volume of distribution, Vd
• The apparent volume of distribution, Vd , is
defined as the volume of fluid required to
contain the total amount, A, of drug in the
body at the same concentration as that
present in plasma, Cp,
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The area under the curve (AUC)
• The area under the curve (AUC) is often used to
determine how much of the drug actually
penetrates the membrane barrier (e.g., skin
or gastrointestinal tract) and gets into the
blood stream.
Absolute Bioavailability, F
• The area under the curve (AUC) of the
concentration-time profiles for oral or
dermal routes is compared with the AUC
for IV routes of administration.
• absolute bioavailability, F:
Clearance
• Clearance(清除率） is defined as the rate
of toxicant excreted relative to its plasma
concentration,
Or 单位时间清除的表观分布容积
• Rate of Excretion（消除速度）
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Section 3
Principles of
biotransformation of
xenobiotics
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Definition
• Conversion of lipophilic xenobiotics to
water-soluble chemicals by a process
catalyzed by enzymes in the liver and
other tissues.
• In most cases, biotransformation lessens
the toxicity of xenobiotics, but many must
undergo the process to exert their toxic
effects.
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General principles
• Broad specificity of xenobiotic
biotransforming enzymes such as P450
enzymes.
• Biotrasformation versus metabolism
• Sterrochemical difference of
biotransformation may lead to different
metabolites
• Phase I and Phase II biotransformation
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Section 4
Phase I and phase II
biotransformation
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Phase I biotransformation
• Hydrolysis: functional group such as carboxylic
羧基,acid ester, amide, thioester, acid anhydride
• Reduction: azo- and nitro-, carbonyl, disulfide,
sulfoxide, quinone, dihydropyrimidine
• Oxidation: alcohol, aldehyde, ketone,
monoamine, aromatization, molybdenum, flavin
Key oxidation enzyme: cytochrome P450
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Cytochrome P450
• Activation of xenobiotics by P450 leads in most
cases to detoxication, but some toxicities like
tumorigenicity of a chemical depends on its
activation.
• Some P450 enzymes in human liver microsomes
are inducible which usually lowers blood level of
the xenobiotics.
• Inhibition of P450 falls into 3 categories: the
competition between 2 chemicals metabolized by
the same P450; by different P450; and by
suicide inactivation.
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Cytochrome P450
subtrate(R H)  O 2  NADPH  H   products(R OH)  H 2 O  NADP 
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Phase II biotransformation
• Reactions: glucuronidation, sulfonation,
acetylation, methylation
• Conjugation with glutathione and amino acid
can result in a large increase in xenobiotic
hydrophilicity to greatly promote the excretion
of foreign chemicals
• Most phase II biotransforming enzymes are
mainly located in the cytosol, and the reactions
are much faster than phase I reactions
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