Factors Affecting Distribution and Metabolism

Chemical Factors Lipophilicity Structure Ionization Chirality

Biological Factors 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 species- dependent 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 N- acetyltransferase 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.