Absorption, Distribution

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• Absorption, Distribution Biotransformation
• II. Biotransformation
• Microsomal enzymes
• Phase I reactions (hydrolysis,oxidations)
• Phase II reactions (conjugations)
• Tissue specificity (eg. MeOH)

• III. Mixtures
• Synergisms (examples and mechanisms)
• Antagonsims (examples mechanisms)

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• Biotransformation
• Enzyme mediated
• Prerequisite to excretion (incr. water
  solubility)
• Rarely complete to CO2 H2O
• Metabolites can be more toxic

• Microsomal Enzymes
• Smooth endoplasmic reticulum (espec. liver)
• Generalist enzymes
• Phase I Phase II Excretion
• (oxidation, hydrolysis) (conjugation)

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Phase I Reactions 1. Esterases (eg.
organophosphate)
S
- P O -
R
Esterase H2O
S
- P OH
HO
R
acid
alcohol
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• 2. P450 Mono-oxygenases (mixed function
  oxygenases)
• Embedded in smooth ER
• Require NADPH, O2

Chem
Chem-OH H2O
NADPH2
P450
NADPH
Chem-P450
O2
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Phase II Reactions Conjugations (eg. glutathione
conjugation
GSH tri-peptide -scavenges reactive
compounds Chem GSH Chem-GSH
Glutathione transferase
Very polar

• Excretion
• Plants- vacuoles
• Animals- urine, bile, eggs, milk, sweat

Tissue Specificity (eg. MeOH)
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• Mixtures
• Additive
• Synergize
• Antagonize

Synergism
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• Synergism
• potentiates another toxin
• How?

• Incr. rate of uptake
• Combine to form toxic metabolites
• Reduce excretion
• Inhibit detotoxification

Ex alcohol barbituates, MalathionEPN,
piperonyl butoxide
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• Antagonism
• neutralizes another toxin
• How?

• Chemical inactivation (complexes or chelation)
• Induction of microsomal detox enzymes
• Block receptor site for other toxin

Ex Atropine as antidote for OP poisons
Organochlorines, Ops induce MFOs EDTA
chelates lead
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