DISPOSITION OF CHEMICALS

1
(No Transcript)
2
DISPOSITION OF CHEMICALS
The disposition of chemicals entering the body
(from C.D. Klaassen, Casarett and Doulls
Toxicology, 5th ed., New York McGraw-Hill, 1996).
3
Plasma concentration vs. time profile of a single
dose of a chemical ingested orally
Plasma Concentration
Time
4
(No Transcript)
5
LOCUS OF ACTION RECEPTORS
TISSUE RESERVOIRS
Bound
Free
Free
Bound
ABSORPTION
EXCRETION
Free Drug
SYSTEMIC CIRCULATION
Bound Drug
BIOTRANSFORMATION
6
Transfer of Chemicals across Membranes

• Passive transport determined by
• - Permeability of surface
• - Concentration gradient
• - Surface area
• Permeability depends on
• For cell membranes
• - Lipid solubility
• - pH of medium
• - pK of chemical
• For endothelium
• size, shape and charge of chemical

PASSAGE ACROSS MEMBRANES
Active
Passive
Facilitated
7
(No Transcript)
8
Factors Affecting Absorption (G.I., lungs, skin)

• Determinants of Passive Transfer (lipid
  solubility, pH, pK, area, concentration
  gradient).
• Blood flow to site.
• Dissolution in the acqueous medium surrounding
  the absorbing surface.

9
Factors Affecting Absorption from the GI Tract

• Disintegration of dosage form and dissolution of
  particles
• Chemical stability of chemical in gastric and
  intestinal juices and enzymes
• Motility and mixing in GI tract
• Presence and type of food
• Rate of gastric emptying
• Intestinal vs. gastric absorption
• FIRST PASS EFFECT

10
Absorption from the Lungs

• For gases, vapors and volatile liquids, aerosols
  and particles
• In general large surface area, thin barrier,
  high blood flow rapid absorption
• Bloodair partition coefficient
• influence of respiratory rate and blood flow
• Bloodtissue partition coefficient

11
Absorption from the Lungs
REMOVAL OF PARTICLES
Absorption of Aerosols and Particles 1-
Particle Size 2- Water solubility of the
chemical present in the aerosol or particle
Lymph
Physical
Phagocytosis
12
DEPOSITION OF PARTICLES IN THE RESPIRATORY SYSTEM
NasopharyngealRegion 5-30 µm
Trachea Bronchi Bronchioles 1-5 µm
Alveolar Region 1 µm
13
Absorption from the Skin

• Must cross several cell layers (stratum corneum,
  epidermis, dermis) to reach blood vessels.
• Factors important here are
• lipid solubility
• hydration of skin
• site (e.g. sole of feet vs. scrotum)

14
Other Routes of Exposure

• Intraperitoneal
• large surface area, vascularized, first pass
  effect.
• Intramuscular, subcutaneous, intradermal
  absorption through endothelial pores into the
  circulation blood flow is most important other
  factors
• Intravenous

15
Bioavailability
Definition the fraction of the administered
dose reaching the systemic circulation for
i.v. 100 for non i.v. ranges from 0 to
100 e.g. lidocaine bioavailability 35 due to
destruction in gastric acid and liver
metabolism First Pass Effect
16
Bioavailability
Destroyed in gut
Not absorbed
Destroyed by gut wall
Destroyed by liver
Dose
to systemic circulation
17
Bioavailability
Plasma concentration
(AUC)o (AUC)iv
i.v. route
oral route
Time (hours)
18
Principle
For chemicals taken by routes other than the
i.v. route, the extent of absorption and the
bioavailability must be understood in order to
determine whether a certain exposure dose will
induce toxic effects or not. It will also
explain why the same dose may cause toxicity by
one route but not the other.
19
Distribution into body compartments

• Plasma 3.5 liters. (heparin, plasma expanders)
• Extracellular fluid 14 liters.
• (tubocurarine, charged polar compounds)
• Total body water 40 liters. (ethanol)
• Transcellular small. CSF, eye, fetus (must
  pass tight junctions)

20
Distribution

• Rapid process relative to absorption and
  elimination
• Extent depends on - blood flow - size,
  M.W. of molecule - lipid solubility and
  ionization - plasma protein binding - tissue
  binding

21
Distribution

• Initial and later phases
• initial determined by blood flow
• later determined by tissue affinity
• Examples of tissues that store chemicals
• fat for highly lipid soluble compounds
• bone for lead

22
Distribution

• Blood Brain Barrier characteristics
• 1. No pores in endothelial membrane
• 2. Transporter in endothelial cells
• 3. Glial cells surround endothelial cells
• 4. Less protein concentration in interstitial
  fluid
• Passage across Placenta

23
Alter plasma binding of chemicals
1000 molecules
90.0
99.9
bound
100
1
molecules free
100-fold increase in free pharmacologically
active concentration at site of
action. NON-TOXIC
TOXIC
24
PRINCIPLE
Chemicals appear to distribute in the body as if
it were a single compartment. The magnitude of
the chemicals distribution is given by the
apparent volume of distribution (Vd).
Amount of drug in body
Vd
Concentration in Plasma
25
Volume of Distribution
Volume into which a drug appears to
distribute with a concentration equal to its
plasma concentration
26
(No Transcript)
27
Examples of apparent Vds for some drugs
28
(No Transcript)
29
Elimination by the Kidney

• Excretion - major 1) glomerular filtration
• glomerular structure, size constraints,
  protein binding
• 2) tubular reabsorption/secretion
• - acidification/alkalinization,
• - active transport, competitive/saturable,
  organic acids/bases -protein binding
• Metabolism - minor

30
Nephron Structure
The structure of the nephron (from A.C. Guyton,
Textbook of Medical Physiology, Philadelphia,
W.B. Saunders Co. 1991
31
Elimination by the Liver

• Metabolism - major
• 1) Phase I and II reactions 2) Function
  change a lipid soluble to more water soluble
  molecule to excrete in kidney
• 3) Possibility of active metabolites with same
  or different properties as parent molecule
• Biliary Secretion active transport, 4 categories

32
The enterohepatic shunt
Drug
Liver
Bile formation
Bile
duct
Biotransformation glucuronide produced
Hydrolysis by beta glucuronidase
gall bladder
Portal circulation
Gut
33
EXCRETION BY OTHER ROUTES

• LUNG - For gases and volatile liquids by
  diffusion.
• Excretion rate depends on partial pressure of
  gas and bloodair partition coefficient.
• MOTHERS MILK
• a) By simple diffusion mostly. Milk has high
  lipid content and is more acidic than plasma
  (traps alkaline fat soluble substances).
• b) Important for 2 reasons transfer to baby,
  transfer from animals to humans.
• OTHER SECRETIONS sweat, saliva, etc..
• minor contribution

34
CLINICAL TOXICOKINETICS

• Quantitative Aspects of Toxicokinetics

35
(No Transcript)
36
Influence of Variations in Relative Rates of
Absorption and Elimination on Plasma
Concentration of an Orally Administered Chemical
Plasma concentration
37
Elimination

• Zero order constant rate of elimination
  irrespective of plasma concentration.
• First order rate of elimination proportional to
  plasma concentration. Constant Fraction of drug
  eliminated per unit time.
• Rate of elimination constant (CL) x Conc.

38
Zero Order Elimination Pharmacokinetics of Ethanol

• Mild intoxication at 1 mg/ml in plasma
• How much should be taken in to reach it?
• 42 g or 56 ml of pure ethanol (Vd x Conc.)
• Or 120 ml of a strong alcoholic drink like
  whiskey
• Ethanol has a constant rate of elimination of
• 10 ml/hour
• To maintain mild intoxication, at what rate must
  ethanol be taken now?
• at 10 ml/h of pure ethanol, or 20 ml/h of drink.

DRUNKENNESS
RARELY DONE
39
First Order Elimination
dC/dt k
-Kel.t
Ct Co e
lnCt lnCo Kel .t
logCt logCo - Kel . t
2.303
Plasma concentration
y b a.x
40
(No Transcript)
41
10000
Zero Order Elimination
1000
Plasma Concentration
100
10
1
0
1
2
3
4
5
6
Time
logCt logCo - Kel . t
2.303
42
Plasma Concentration Profile after a Single I.V.
Injection
43
lnCt lnCo Kel.t
Vd Dose/C0
When t 0, C C0, i.e., the concentration at
time zero when distribution is complete and
elimination has not started yet. Use this value
and the dose to calculate Vd.
44
lnCt lnCo Kel.t
t1/2 0.693/Kel
When Ct ½ C0, then Kel.t 0.693. This is the
time for the plasma concentration to reach half
the original, i.e., the half-life of elimination.

45
Principle

• Elimination of chemicals from the body usually
  follows first order kinetics with a
  characteristic half-life (t1/2) and fractional
  rate constant (Kel).

46
First Order Elimination

• Clearance volume of plasma cleared of chemical
  per unit time.
• Clearance Rate of elimination/plasma conc.
• Half-life of elimination time for plasma conc.
  to decrease by half.
• Useful in estimating - time to reach
  steady state concentration. - time for plasma
  conc. to fall after exposure stopped.

47
Rate of elimination Kel x Amount in body Rate
of elimination CL x Plasma Concentration
Therefore, Kel x Amount CL x
Concentration Kel CL/Vd 0.693/t1/2 CL/Vd

t1/2 0.693 x Vd/CL
48
Principle

• The half-life of elimination of a chemical (and
• its residence in the body) depends on its
• clearance and its volume of distribution
• t1/2 is proportional to Vd
• t1/2 is inversely proportional to CL

t1/2 0.693 x Vd/CL
49
Multiple dosing

• On continuous steady administration of a
  chemical, plasma concentration will rise fast at
  first then more slowly and reach a plateau,
  where
• rate of administration rate of elimination
  ie. steady state is reached.
• Therefore, at steady state
• Dose (Rate of Administration) clearance x
  plasma conc.
• or
• steady state conc. Dose/clearance

50
(No Transcript)
51
Single dose
Toxic level
Cumulation
plasma conc
Time
52
The time to reach steady state is 4 t1/2s
Concentration due to repeated doses
Concentration due to a single dose
53
Pharmacokinetic parameters

• Vol of distribution V DOSE / Co
• Plasma clearance Cl Kel .Vd
• plasma half-life (t1/2) t1/2 0.693 / Kel or
  directly from graph
• Bioavailability (AUC)x / (AUC)iv

54
dX/dt CL x Conc.
dX CL x Conc. x dt
But Conc. x dt small area under the curve. For
total amount eliminated (which is total given or
the dose if i.v.), add all the small areas AUC.
Dose CL x AUC and Dose x F CL x AUC
55
(AUC)o (AUC)iv
Bioavailability

i.v. route
oral route
Plasma concentration
Time (hours)
56
Variability in Pharmacokinetics
60
50
40
Concentration (mg/L)
Plasma Drug
30
20
10
0
0
5
10
15
Daily Dose (mg/kg)
57
PRINCIPLE

• The absorption, distribution and elimination of
  a chemical are qualitatively similar in all
  individuals. However, for several reasons, the
  quantitative aspects may differ considerably.
  Each person must be considered individually and
  treated accordingly.

58
(No Transcript)
59
THE DOSE-RESPONSE RELATIONSHIP
The dose-response relationship (from C.D.
Klaassen, Casarett and Doulls Toxicology, 5th
ed., New York McGraw-Hill, 1996).