Dennis Paul, Ph.D. Department of Pharmacology 504-568-4740 rwainf@lsuhsc.edu

1. BIOLOGICAL SYSTEM AGastrointestinal and Hepatic SystemsRegulation of Drug Transport, Absorption, Distribution, Excretion and Metabolism Dennis Paul, Ph.D. Department of Pharmacology 504-568-4740 rwainf@lsuhsc.edu

2. Principles of Pharmacology • Common processes and mechanisms whereby: • Drugs gain access to the body • Drugs move throughout the body • Drugs produce an effect by altering • a physiological process • Drugs are removed from the body

3. Pharmacokinetics The study of drug movement into, within and out of the body, which includes absorption, distribution, metabolism and elimination

4. Pharmacokinetics: • Absorption: Transfer of drug from site of administration to systemic circulation • Distribution: Transfer of drug from systemic circulation to tissues • Metabolism: Alteration of drug to increase excretion from the body • Excretion: Drug movement out of the body

6. Routes of drug administration Affects onset and duration of drug 1) Enteral – directly into G.I. tract Oral or rectal administration - safest, cheapest, most convenient • slow onset, sometimes unpredictable response 2) Parenteral – bypasses G.I. tract Usually injection, can be inhalation or topical administration - fast absorption, rapid onset, predictable response - more expensive, more difficult, painful, requires sterile conditions

7. Oral route (enteral) ● Advantages -Most common, convenient, painless and inexpensive way to administer a variety of drugs e.g. liquid, tablet, coated tablet etc -GI tract a large blood rich absorbent surface ● Disadvantages -First pass metabolism Drug must pass through GI tract and liver before entering circulation and therefore are subject to metabolism meaning higher doses are given orally e.g. morphine -Food and GI motility affects absorption – must comply with instructions e.g. with food or on empty stomach -Can be difficult to predict percentage of active drug that reaches patient

8. Rectal route (enteral) • Usually suppository, cream or enema e.g. aspirin, barbituates • Drug mixed with waxy substance that dissolves in the rectum • Advantages • -Reduced first pass metabolism, some rectal veins lead into direct circulation bypassing liver • -Used in patients unable to take drugs orally e.g. elderly, young, unconscious • Disadvantages • -Not well liked by patients • -Absorption very variable so not reliable method of drug delivery

9. Drug Profiles [Drug] Physical Properties Structure Lipid solubility Ionization state Time (h)

10. Objectives • Mechanisms of drug transport • Drug absorption • Drug distribution • Drug metabolism • Drug excretion

11. Mechanisms of Drug Transport • Passive diffusion • Passive diffusion of non-electrolytes • Passive diffusion of electrolytes • Filtration • Carrier-mediated transport • Active transport • Facilitated diffusion • Receptor-mediated endocytosis • Ion-pair transport Endogenous compounds and drugs

12. Mechanisms of Drug Transport • Passive diffusion – Low molecular weight drugs that are both water and lipid soluble dissolve in membrane and cross to the other side. • Primary means by which drugs cross membranes

13. Mechanisms of Drug Transport • Passive Diffusion • Drugs dissolve and cross the cell membrane following concentration gradient. • Characteristics of drugs that use passive diffusion: ● Small ● Predominantly lipid soluble ● Uncharged ● Small water soluble molecules pass via pores

14. Mechanisms of Drug Transport • Passive diffusion • 1) Passive diffusion of non-electrolytes • 2) Passive diffusion of electrolytes • Influence of pH and pka • Weak acids are uncharged in acidic environment • Weak bases are uncharged in basic environment

15. Mechanisms of Drug Transport • Passive diffusion • Passive diffusion of non-electrolytes • Lipid-water partition coefficient (Kp) -the ratio of the concentration of the drug in two immiscible phases: a nonpolar liquid (representing membrane) and an aqueous buffer (representing the plasma). • Kp can be measured. Kp = [drug] in lipid phase/[drug] in aqueous phase. • If the drug is more soluble in the lipid, Kp is higher. If the drug is more soluble in the aqueous phase, Kp will be lower. • The partition coefficient is a measure of the relative affinity of a drug for the lipid and aqueous phases. • One can control the Kp by modifying the side groups on the compound. The more C and H on the compound, the more lipid soluble, and thus the higher the Kp. The more O, S and the more water-soluble the compound, and the lower the Kp.

16. Mechanisms of Drug Transport • Passive diffusion of non-electrolytes: • The higher the Kp, the more lipid soluble, the faster the rate of transfer across biological membranes

17. Mechanisms of Drug Transport • 2) Passive diffusion of electrolytes • pKa: the pH at which half of the molecules are in the ionized form and one half are in the unionized form. • pKais a characteristic of a drug. • Henderson-Hasselbalchequations: • For acids: pH = pKa + log [A-]/[HA] • For bases: pH = pKa + log [B]/[BH+]

18. Mechanisms of Drug Transport 2) Passive diffusion of electrolytes HA H+ + A- BH+ H+ + B pH < pKa Predominate forms: HA and BH+ pH > pKa Predominate forms: A-and B pH = pKa HA = A- BH+ = B pH 3 4 5 6 7 8 9 10 11

19. Mechanisms of Drug Transport • 2) Passive diffusion of electrolytes • Only the unionized forms of the drug or the uncharged drug can pass through or across the membranes (or is transferred) by passive diffusion. • Un-ionized form acts like a nonpolar lipid soluble compound and can cross body membranes • Ionized form is less lipid soluble and cannot easily cross body membranes • By controlling the pH of the solution and/or the pKa of the drug, you can control the rate at which the drug is transferred

20. Mechanisms of Drug Transport • Drugs that are weak electrolytes equilibrate into ionized and non-ionized forms in solution • pH (H+ concentration) at site of administration and the dissociation characteristics (pKa) of the drug determine the amount ionized and non-ionized drug

21. Mechanisms of Drug Transport ASPIRIN pKa = 4.5 (weak acid) 100mg orally 1 = [ I ] H+ + A- Stomach pH = 2 Blood pH = 7.4 99 = [ UI ] HA Aspirin is absorbed from stomach (fast action)

22. Mechanisms of Drug Transport Aspirin accumulation [ UI ] [ I ] Acidic drug - pKa = 4.5 1 0.01 HA H+ + A- pH = 2 Body compartment 1 - stomach Membrane Body compartment 2 – blood HA H+ + A- pH = 7.4 1 100 [ UI ] [ I ]

23. Mechanisms of Drug Transport STRYCHNINE pKa = 9.5 (weak base) 100mg orally H+ + B 99 = [ I ] Blood pH = 7.4 Stomach pH = 2 1 = [ UI ] HB+ Strychnine not absorbed until enters G.I. tract

24. Mechanisms of Drug Transport 2. Filtration - Passage of molecules through membrane pores or porous structures.

25. Mechanisms of Drug Transport • The rate of filtration • Driving force: The pressure gradient in both sides. • The size of the compound relative to the size of the pore. • Smaller compound – transfer rapidly • Larger compound – retained • Intermediate compound – barrier Lipid soluble – passive diffusion Water soluble – filtration

26. Mechanisms of Drug Transport • The rate of filtration: • In biological systems: Filtration is the transfer of drug across membrane through the pores or through the spaces between cells • Capillary endothelial membranes • Renal glomerulus • Most substances (lipid-soluble or not) – cross the capillary wall – very fast • Lipid soluble and unionized – filtration and passive diffusion – at the same time

27. Mechanisms of Drug Transport • 3. Carrier-mediated transport A. Active transport • Goes against concentration gradient • Requires energy (ATP) • Mediated by transport carrier proteins • Drug combines with a transport protein in the membrane and the complex can move across the membrane • Selectivity - not for all drugs • One-way process – against drug concentration gradient resulting in drug accumulation • It can be saturated – Drug/receptor ratio – enzyme-catalyzed reactions • Can be inhibited – ATP inhibitors, structural analogous compounds

28. Mechanisms of Drug Transport • 3. Carrier-mediated transport • b. Facilitated diffusion • Carrier or receptor-mediated • Selective to specific molecules e.g. glucose • It can be saturated • Does not require ATP • Does not go against the concentration gradient • Bi-directional – no drug accumulation

29. Mechanisms of Drug Transport • 4. Receptor-mediated endocytosis • - more specific uptake process • Drugs (peptide hormones, growth factors, antibodies, et al.) bind to their receptors on the cell surface in coated pits, and then the ligand and receptors are internalized, forming endosomes. • Receptor-ligand complex may take four different pathways: • Receptor recycles, ligand degraded • Receptor and ligand recycle • Receptor and ligand degraded • Receptor and ligand transported

31. Mechanisms of Drug Transport 5. Ion-pair transport Highly ionized Passive diffusion + + _ _ + + _ _ Carrier

32. Pharmacokinetics: Absorption • Process by which drug molecules are transferred from administration site to systemic circulation • Factors affecting absorption: 1. site of GI absorption 2. modifications • Bioavailibility • Solubility of drug e.g. suspension absorbed more slowly than a solution, solubility = absorbance

33. Drug Absorption • 1. Sites of absorption through the GI tract • Mouth • Stomach • Small intestine • Large intestine

34. Drug Absorption • 1) Mouth: • Small amount of surface area but good blood flow – best for potent drugs. • Transfer by passive diffusion – good for lipid soluble drugs. • pH = 6. Weak base drugs have better absorption. • Nicotine pKa 8.5 Mouth GI tract • pH 6 1-5 • Ionization less ionized ionized • Absorption 4 times faster • d. Can bypass first pass effect.

35. Drug Absorption • 2) Stomach: • Moderate surface area – more than mouth, less than small intestine. • Good blood supply. • Drugs absorbed in the stomach will experience first pass effect. • Transfer by passive diffusion. • Low pH (1-2) – ionization - Drugs that are weak acids will be absorbed better than weak base drugs. • Ion trapping: Accumulation of weak base drugs in the stomach.

36. Drug Absorption • 3) Small intestine • The primary site for most drugs. • Large surface area - Folds, villi and microvilli. • pH = 5-8. • Passive diffusion. • Absorption can also take place by active transport, facilitated diffusion, endocytosis and filtration.

37. Drug Absorption • 4) Large intestine • Not important for drug absorption, if the drug is absorbed effectively in small intestine. • Can be a site of absorption for incompletely absorbed drugs. • Less absorption then small intestine – less area and solid nature of contents.

38. Drug Absorption • 2. Factors that modify absorption in the GI tract • 1) Drug solubilization • 2) Formulation factors • 3) Concentration of drug at the absorption site • 4) Blood flow at the absorption site • 5) Surface area of absorption small intestine • 6) Route of administration • 7) Gastric emptying • 8) Food • 9) Intestinal motility • 10) Metabolism of drug by GI tract

39. Drug Absorption 1) Drug solubilization – breaking drugs into smaller, more absorbable particles Hydrophilic drugs - poorly absorbed - inability to cross the lipid-rich cell membrane. Hydrophobic drugs - poorly absorbed - insoluble in the aqueous body fluids - cannot gain access to the surface of cells. - largely hydrophobic yet have some solubility in aqueous solutions. Solid Granules fine particles: disintergration deaggregation Solution

40. Drug Absorption 2) Formulation factors – materials added to the drug during processing can affect the solubilization of the drug. a. Fillers – add bulk to the tablet b. Disintegrators – cause table to break down into granules c. Binders – hold tablet together d. Lubricants – prevent tablet from sticking to machinery Formulation factors - not clinically important if the drug is absorbed effectively and may have important influence on drug absorption for these drugs which are not effectively absorbed in the GI tract - influence drug’s bioavailability.

41. Drug Absorption • 3) Concentration of drug at the absorption site • Passive diffusion • Driving force – the concentration gradient. • The higher the concentration of the drug, the faster the rate of absorption.

42. Drug Absorption • 4) Blood flow at the absorption site • - maintain concentration gradient Membrane Blood

43. Drug Absorption • 5) Surface area of absorption small intestine

44. Drug Absorption • 6) Route of administration • GI tract – first pass effect

45. Drug Absorption • 7) Gastric emptying • small intestine – primary site of drug absorption • Anything that delays/accelerates gastric emptying will decrease/increase drug absorption. • For all drugs - acidic, basic or neutral substances.

46. Drug Absorption • 8) Food • High fat food – delay gastric emptying – slow absorption

47. Drug Absorption • 9) Intestinal motility • – depends on whether the drug is completely absorbed under normal condition. • a. Completely absorbed early upon entry into the small intestine, increasing intestinal motility will not significantly affect absorption. • b. Not completely absorbed before entry into the small intestine, increasing/decreasing intestinal motility will slow down/facilitate drug absorption.

48. Drug Absorption • 10) Metabolism of drug by GI tract • a. Drug metabolizing enzymes in the GI tract • b. Proteases in the GI tract • c. Microbes in the GI tract - metabolize certain drugs • - Drug metabolites are not usually absorbed.

49. Absorption: Bioavailability • Bioavailability: fraction of oral dose that appears in systemic circulation. • Unless given as liquid, drug must be released by: • Disruption of coating or capsule • Disintegration of tablet • Dispersion throughout stomach or G.I. tract • Dissolution in gastrointestinal fluid