Transportation and Transformation of Xenobiotics

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Transportation and Transformation of Xenobiotics
Chapter 3
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• lung

• feces

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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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Absorption
Section 1
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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
• Cytosisendocytosis 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
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(???)and
  parenteral routes.

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Factors Altering the GI Absorption of Toxicants

• pH of the GI ????????????
• Residency time of compounds
• Physical properties of chemicals ???????
• First-pass effect
• ??????????????????????????????????(?????),????????
  ???????,?????????(first-pass elimination)???????,?
  ????(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??? ) 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 (?????????????)
• 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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Distribution and Excretion
Section 2
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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 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)
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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
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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.

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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

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Clearance

• Clearance(???) is defined as the rate of toxicant
  excreted relative to its plasma concentration,
• Or ?????????????
• Rate of Excretion(????)

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Principles of biotransformation of xenobiotics
Section 3
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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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Phase I and phase II biotransformation
Section 4
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Phase I biotransformation

• Hydrolysis functional group such as
  carboxylic??,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
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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