Disposition of Chemical Compounds

1. Disposition of Chemical Compounds

2. Four Phases To Disposition of Chemical Compounds • Absorption of Chemicals into the Body • Distribution of Chemicals within the Body • Metabolism of Chemicals within the Body • Excretion of Chemicals from the Body

3. Absorption of Chemical Compounds • The most common means of entry of chemical compounds include: • Digestive Tract (Oral) • Lungs or Gills (Inhalation) • Skin (Dermal) • Other Routes • Intraperitoneal, intramuscular, subcutaneous, intravenous

4. Absorption - Continued • Absorption necessarily involves the passage of compounds across membranes. Therefore, membrane structure and transport processes are important issues.

5. Absorption - Continued • Transport Across Membranes • Filtration • Passive Diffusion • Active Transport • Facilitated Diffusion • Phagocytosis/Pinocytosis

6. Absorption - Continued • The most common transport process for absorption of chemical compounds in passive diffusion. • Depends upon diffusion through phospholipid bilayer • Must be a [ ] gradient across membrane • Compound must be lipid soluble • Compound must be in non-ionized state

7. Absorption - Continued • Absorption of compounds by diffusion will follow Fick’s Law • Rate of diffusion = KA (C2 – C1) d The concentration gradient will normally be maintained and an equilibrium will not be reached. The concentration on the inside of the membrane will be continually decreasing as a result of ionization, metabolism, and distribution to another compartment.

8. Absorption - Continued • Passive diffusion relies on dissolution of the compound in the lipid component of the membrane and therefore only lipid soluble (lipophilic) compounds will pass through the membrane. • Lipid Solubility measured by Octanol – Water Partition Coefficient (Kow) • Lipophilic compounds have a Kow = 100 to 1,000,000 • Log Kow value is used so Kow = 2 to 6 for lipophilic compounds • Very lipophilic compounds --- Kow > 6 may get stuck in membrane and not be absorbed as readily as Kow 2 to 6 compounds

9. Absorption - Continued • Active and Facilitated Transport: • a specific membrane carrier system is required • the process may be saturated at high substrate concentrations • substrates may compete for uptake • 5-fluorouracil, an anticancer drug, is absorbed by the pyrimidine transport system • Lead is absorbed by the calcium transport system

10. Absorption – Continued-Compartments

11. Sites of Absorption • Digestive Tract • This is one of the most important sites of absorption because many substances are in the food that we eat; also for drugs we take • If a compound is a weak acid or a weak base, the compound is mainly absorbed from the part of the digestive tract in which the compound exists in the non-ionized form (the most lipid soluble form). • Handout for Students!

12. Absorption – Continued-Acids and Bases

13. Digestive Tract - Continued • The amount of the chemical that enters the systemic circulation after oral administration depends upon: • The amount absorbed into digestive tract cells • The amount metabolized (bio-transformed) by digestive tract cells • The amount extracted by the liver – termed the “first pass effect”

14. Lungs • Gases, vapors of volatile compounds, particulate matter • For compounds with a low solubility in blood – the rate of transfer from air (in alveolus) to blood will be mainly dependent on blood flow (perfusion limited) • For compounds with a high solubility in blood – the rate of transfer from air (in alveolus) to blood will be mainly dependent on respiration rate (ventilation limited)

15. Lungs - Continued • Particulate matter

16. Skin • Skin is not very permeable but some compounds can penetrate skin (nerve gases, some insecticides, carbon tetrachloride) • Compounds must pass through epidermis, sweat/sebaceous glands or hair follicles; most movement is through epidermis

17. Distribution of Chemical Compounds With Body • Compounds are distributed to various tissues by the plasma • Distribution is a very complex process and the final distribution of a particular compound depends largely on the affinity of the compound for various tissues • Important Point! – The site of highest [ ] of a compound is not necessarily the site of toxic action

18. Absorption – Continued-Compartments

19. Distribution - Continued • Storage of Compounds • Plasma Proteins • There are a number of proteins in plasma that can reversibly bind various chemical compounds • Most compounds that bind to plasma proteins bind to albumin – albumin has 6 different binding regions • Environmental chemical and drugs can compete with and displace endogenous compounds that are bound to plasma proteins • Environmental chemicals and drugs can compete with each other for binding sites and displace eachother

20. Distribution - Continued • Storage of Compounds • Liver and Kidney • These two organs concentrate more chemical compounds than all other organs combined • Ligandin (binds weak acids) and Metallothionein (binds metals) are two proteins that concentrate in the liver and kidneys

21. Distribution - Continued • Storage of Compounds • Adipose Tissue • Many toxic compounds are highly lipophilic and they accumulate in adipose tissue by dissolution in neutral fats (triglycerides) • Adipose tissue can constitute ~ 50% of body weight in obese people and ~ 20% of body weight in lean people • Issue with migrating and hibernating animals, significant weight loss

22. Distribution - Continued • Storage of Compounds • Bones • Compounds such as fluoride, lead, and strontium accumulate in bone • 90% of lead in the body is eventually found in the skeleton • Fluoride displaces OH- • Lead and strontium displaces Ca++

23. Distribution - Continued • Storage of Compounds • Central Nervous System • Compounds entering the Central Nervous System must pass the Blood-Brain Barrier • Increased lipid solubility increases rate of chemical entry into CNS while ionization decreases rate of entry (passive diffusion) • Some chemical compounds (very few) enter the CNS by carrier transport processes, ex. Methylmercury combines with cystein forming a compound similar to methionine and then compound is actively transported into CNS • Blood Brain Barrier is not fully formed in infants – therefore some compounds like morphine and lead are much more toxic to infants than to adults

24. Distribution - Continued • Storage of Compounds • Fetus • Many compounds (especially lipophilic compounds) can cross the placenta • Placenta has metabolizing (bio-transformation) ability so some compounds might not reach fetus • Fetus has little fat so fetus does not accumulate large amounts of lipophilic compounds

25. Excretion of Chemical Compounds • Excretory Pathways: • Kidney (Urinary Excretion) • Digestive Tract (Fecal Excretion) • Lungs • Others • Sweat • Hair • Milk

26. Excretion - Continued • Urinary Excretion • Compounds with high lipid solubility (non-ionized) will be reabsorbed from the nephron back into the plasma • Compounds that are ionized will tend to be excreted • Bases are excreted better at a lower urinary pH • Acids are excreted better at a higher urinary pH • Ex. Phenobarbital poisoning (weak acid) – treated using sodium bicarbonate to increase urinary pH

27. Excretion - Continued • Urinary Excretion • Because some kidney functions are not fully developed at birth, some compounds are excreted more slowly in infants than in adults • Ex. Penicillin – excreted at 20% rate of adult • Proximal tube cells reabsorb small proteins – Cadmium and mercury attached to metallothionein enter proximal tube cells, remain in cells and kill cells

28. Excretion - Continued • Fecal Excretion • Some percentage of chemicals ingested pass through digestive tract unabsorbed • The biliary route is the most important mechanism for excretion from digestive tract • Bile production occurs in the liver, bile flows to bile duct and then to small intestine

29. Excretion - Continued • Fecal Excretion • Factors that affect excretion by digestive tract • Molecular weight of the chemical compound • Charge on the chemical compound • Animal species

30. Excretion - Continued • Fecal Excretion • Molecular weight of chemical • MW of 300 or more give significant excretion through bile. The exact cutoff varies with species

31. Excretion - Continued

32. Excretion - Continued • Fecal Excretion - Continued • Charge on compound • If the compound stay ionized at pH of small intestine little of the compound will be reabsorbed • If the compound becomes non-ionized at pH of small intestine then compound will be reabsorbed, called Enterohepatic Circulation • Enterohepatic Circulation • Microflora in the gut can metabolize the chemical back to a lipid soluble form – chemical then reaborbed

33. Excretion - Continued

34. Excretion - Continued

35. Excretion - Continued • Lungs • Chemical with low solubility in blood – fast excretion • Chemical with high solubility in blood – slow excretion • Particulate matter involved with “ciliary escalator” or macrophages

36. Excretion - Continued • Other Routes • Sweat and Saliva – Minor importance • Hair – some metals like mercury • Milk – lipophilic substances and some metals such as lead, transfer from mother to infant • Can also be tansfer through consumption of dairy products

37. Concept of Half-Life

38. Half-Life With One Compartment Model

39. Half-Life With Multiple Compartment Model

40. Multiple Dosing of Compounds