Factors Affecting Distribution
and Metabolism
Chemical Factors
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Lipophilicity
Structure
Ionization
Chirality
Biological Factors
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Species
Strain
Sex
Genetic Factors
Disease
Hormomal Influences
Age
Stress
Diet -Enzyme Induction and Inhibition
Species
• Species differences in toxicity of a
compound are often related to differences in
the metabolism and disposition of the
compound.
• Disposition of Compounds
– Absorption
• Absorption of compound through the skin shows
considerable species variation
Disposition
• Absorption
– Oral absorption depends upon pH of digestive
tract (herbivores vs omnivores and carnivores
– Absorption by inhalation depends upon
breathing rate (smaller animals have much
higher ventilation rates than larger animals)
– Absorption depends on whether and how much
food is in the GI tract.
Food  protein binding hinders drug
absorption
Empty stomach  More drug absorption
because:
1. Less protein binding
2. Ketones induce CYP2E1  increased
metabolism of several types of low-MW
xenobiotics (e.g., acetominophen, ethanol,
N-nitrosomethylamine)
Disposition
• Distribution
– The plasma protein concentration is a speciesdependent variable, also types of proteins vary
between species.
• Excretion
– Rate of urine production varies considerable
between species (rat is 10x that of human)
Disposition
• Excretion (Continued)
– The molecular weight cutoff for biliary
excretion shows considerable species variation.
• Thresholds = 325 in rat, 400 in guinea pigs, 475 in
rabbits, and 500 – 700 in humans
– Fate of compounds excreted through bile
depends upon pH of digestive tract segments
and composition of microflora in segments.
Metabolism
• Differences are mainly quantitative but
there are some qualitative differences too
• Small animals metabolize compounds at a
faster rate than large animals per unit body
weight
Metabolism
• Phase I Reactions
– Most common differences are in RATE at
which a particular compound is oxidized but
there are also some pathway differences.
• Examples of pathway differences are shown on next
two slides
– Ethylene Glycol
– Amphetamine
Ethylene Glycol Toxicity
• Production of oxalic
acid is in the order:
– Cat > Rat > Rabbit
– Toxicity of compound
is in same order
– Oxalic acid precipitates
out in the kidney
tubules causing kidney
damage
Amphetamine Toxicity
• Different species of
mammals produce
different major phase I
metabolites of
amphetamine. The
compounds are shown
in this slide.
Malathion Toxicity
• Malathion is
hydrolysed differently
in mammals and in
insects (the target
species for this
insecticide).
– P = S makes a very
ineffective insecticide
– P = O makes a good
insecticide
Metabolism
• Phase II Reactions
– Glucuronide conjugation is an important route
of metabolism in mammals, birds, reptiles, and
amphibians, but not in fish.
– In mammals, cats lack the ability to conjugate
phenols with Glucuronic acid. Cats presumably
lack the enzyme for the reaction.
Metabolism
• Phase II Reactions
– Sulphate Conjugation
• Found in most mammals, birds, reptiles and
amphibians but not in fish
– Amino Acid Conjugation
• Herbivores favor amino acid conjugation, carnivores
favor glucuronide conjugation, and omnivores
utilize both routes of phase II metabolism
Affects of Gender
• Male rats metabolize compounds more rapidly
than do female rats
• Humans are similar to rats in that males
metabolize compounds faster than do females
• Female mice metabolize compounds more rapidly
than do male mice
– Differences between genders are due to hormones and
can be abolished with administration of androgens to
female animals.
Genetic Factors
• Acetylator Phenotype
– Bimodal distribution within human population
in rate of acetylation
– Genetic Polymorphism gives “slow” and “fast”
acetylators
• Single gene trait with “slow” acetylators being a
simple recessive trait (rr = slow, RR or Rr = fast)
• The genetic trait governs the forms of the Nacetyltransferase enzyme
• What if someone were a slow acetylator? What
would this mean in terms of drug disposition?
Genetic Factors
• Hydroxylator Phenotype
– Extensive Metabolizers (DD or Dd)
– Poor Metabolizers (dd)
• Poor metabolizers have exaggreated
pharmacological effect of a therapeutic dose of drug
because of higher plasma level of unmetabolized
drug
• Biochemical basis for trait – almost complete
absence of CYP2D6
Age Effects
• Neonatal and geriatric human subjects have
low gastric acid secretion – leads to change
in absorption patterns
• Neonatal and geriatric human subjects have
lower levels of total plasma proteins, and
lower levels of albumin.
• Form of plasma proteins in neonates
different from adults
Age Effects (Continued)
• Permeability of blood-brain barrier is higher
in newborns
• Both Phase I and Phase II metabolic
reactions show a pattern of development
after birth. It may take a month or more for
some enzyme systems to come to full
activity.