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 (K ow ) Lipophilic compounds have a K ow = 100 to 1,000,000 Log K ow value is used so K ow = 2 to 6 for lipophilic compounds Very lipophilic compounds --- K ow > 6 may get stuck in membrane and not be absorbed as readily as K ow 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. 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

35. 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