Factors Affecting Distribution and Metabolism

1. Factors Affecting Distribution and Metabolism

2. Chemical Factors • Lipophilicity • Structure • Ionization • Chirality

3. Biological Factors • Species • Strain • Sex • Genetic Factors • Disease • Hormomal Influences • Age • Stress • Diet -Enzyme Induction and Inhibition

4. 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

5. 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:

6. Less protein binding • Ketones induce CYP2E1  increased metabolism of several types of low-MW xenobiotics (e.g., acetominophen, ethanol, N-nitrosomethylamine)

7. 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)

8. 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.

9. 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

10. 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

11. 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

12. Amphetamine Toxicity • Different species of mammals produce different major phase I metabolites of amphetamine. The compounds are shown in this slide.

13. 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

14. 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.

15. 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

16. 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.

17. 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?

18. 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

19. 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

20. 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.