DRUG PERMEATION THROUGH INTESTINE

1. DRUG PERMEATION THROUGH INTESTINE Mario Grassi Department of Chemical Engineering (DICAMP) UINVERSITY OF TRIESTE

2. Farmaco BIODISPONIBILITA’ “Frazione della dose di principio attivo che diviene disponibile al sito (fisiologico) di azione dopo somministrazione”

3. INTRODUCTION Delivery system WHICH IS OUR PROBLEM?

4. DRUG RELEASE FROM THE DELIVERY SYSTEM DRUG ABSORPTION AND METABOLISM/EXCRETION TWO ASPECTS MUST BE CONSIDERED

5. SETTING UP OUR PROBLEM Modern Biopharmaceutics, version 6.03, G. L. Amidon, M. Bermejo, TSRL inc, produced by Judy C. Price.

6. Modern Biopharmaceutics, version 6.03, G. L. Amidon, M. Bermejo, TSRL inc, produced by Judy C. Price.

7. 0 – CENTRAL POINT: ADME DISTRIBUTION BLOOD and DEEPER COMPARTMENT METABOLISM ABSORPTION EXCRETION

8. 1 – PHARMACOKINETICS Pharmacokinetics is the study of the time course of drug absorption, distribution, metabolism and excretion (ADME), and how these ADME processes are related to the intensity and time course of the pharmacological (therapeutic and toxic) effects of drugs

9. METABOLISM - EXCRETION Systemic metabolsim Pre-systemic metabolsim Gut metabolism lung Kidney Delivery System Heart Excretion Liver First pass metabolism Excretion Modern Biopharmaceutics, version 6.03, G. L. Amidon, M. Bermejo, TSRL inc, produced by Judy C. Price.

10. SYSTEMIC CIRCULATION F = Fa * Fg * Fh *Fl =BIOAVAILABILITY

11. CLEARANCE Drug elimination Cd “Is the volume of blood that must be cleared of drug per unit time in order to account for drug elimination” Blood flow Q Continuous Drug Supply

12. Cd Q Blood flow Q1 NO DRUG ELIMINATION FILTER Qc Clearing Blood flow Qc= CLEARANCE TOTAL DRUG ELIMINATION

13. C (mass/volume) Cliv= DOSE/AUC AUC T (time) INTRA VINUS CLEARANCE: Cliv

14. Cls = Dose/ AUC Cls = 100 / 0.001 = 104 ml/s ORAL CLEARANCE: Cloral

15. Cloral = Cliv/ (Fa*Fg*Fh* Fl) F = bioavailability

16. Vb = blood volume Vt = issues volume fb = drug unbound fraction in blood ft = drug unbound fraction in tissues DISTRIBUTION VOLUME: V “Is a measure of the extent of drug distribution and is determined by the drug binding in plasma as well as tissues.” V = Vb + Vtfb/ft

17. ELIMINATION HALF TIME: T1/2 Time required to metabolize /excrete half dose T1/2 = 0.693 V/Cls

18. a short section that receives secretions from the pancreas and liver via the pancreatic and common bile ducts Duodenum: considered to be roughly 40% of the small gut in man, but closer to 90% in animals. Jejunum: empties into the large intestine; considered to be about 60% of the intestine in man, but veterinary anatomists usually refer to it as being only the short terminal section of the small intestine. Ileum: 2 – SMALL INTESTINE STRUCTURE The small intestine is the longest section of the digestive tube and consists of three segments forming a passage from the pylorus to the large intestine

19. Small intestine is suspended from the body wall by an extension of the peritoneum called the mesentery. blood vessels to and from the intestine lie between the two sheets of the mesentery. Lymphatic vessels are also present, but are not easy to discern grossly in normal specimens.

20. T. Serosa: In most of the digestive tract (stomach and intestines) it consists of a thin layer of loose connective tissue covered by mesothelium (a type of squamous epithelium that lines body cavities) T. Muscularis: endows the digestive tube with an ability to be motile.

21. T. Submucosa:immediately beneath the mucosa, is a layer of loose to dense connective tissue containing blood and lymphatic vessels T. Mucosa: Among the four tunics, the mucosa is most variable in structure and function, endowing the tube with an ability to perform diverse and specialized digestive tasks along its length. Of critical importance are the epithelial cells that cover the mucosa and are thus in direct contact with the lumen.

22. Substances absorption and much of the enzymatic digestion takes place on the surface of small intestinal epithelial cells, and to accomodate these processes, a huge mucosal surface area is required. Small Intestine macroscopic folding Lumenal surface area ≈ 0.5 m2 Real absorptive surface area ≈ 250 m2

23. Height = 0.5 - 1 mm Diameter = 0.1 mm Height = 1 mm Diameter = 0.1 mm

24. SCHEMATIC REPRESENTATION OF VILLI

25. pH VARIATIONS STOMACH: pH = 1.2 - 2 DUODENUM pH = 4.0 – 5.5 JEJUNUM pH = 5.5 – 7 pH = 5.5 – 7 S. I. Lumen ILEUM STAGNANT LAYER (300 mm) DpH = 0.5 LAYER (≈ 20 mm)

26. 3 – CELLS MEMBRANE STRUCTURE CELLS MEMBRANE: FLUID MOSAIC MODEL The double layer results from the orientation of the amphiprotic lipids (phospholipids, glycolipids, cholesterol) in the aqueous medium

27. In the membrane, different proteins are embedded performing different functions. Some proteins form selective ion-channels (Na+, K+, Ca++, Cl-).

28. By the interaction of membrane proteins at the contact surfaces between single cells so called tight junctions are formed. In most membranes, these tight junctions contain fenestrae, which can be regarded as pores filled with water

29. 4 – ABSORPTION MECHANISMS TIGHT JUNCTIONS APICAL + CATIONS ANIONS - BASOLATERAL PARACELLULAR TRANCELLULAR PASSIVE: DIFFUSION DUE TO CHEMICAL POTENTIAL GRADIENT

30. DRUG MW < 200 TRANSCELLULAR IMPORTANT PARACELLULAR IMPORTANT DRUG MW > 200 TRANSCELLULAR IMPORTANT PARACELLULAR NOT IMPORTANT In the small intestine, the surface area presented by paracellular route constitutes only a small fraction (0.01%) of the total membrane surface area

31. FACILITATED DIFFUSION MEMBRANE PROTEINS (CARRIER C) BIND TODIFFUSANT (AA AMINOACIDS; SUGAR S) IMPROVING ITS DIFFUSION ACROSS CELL MEMBRANE. FdAA and FdS INDICATE AA AND S CONCENTRATION GRADIENT

32. FILTRATION All passive diffusion processes my be superimposed by an osmotic water flow, able to drag along the molecules (= solvent drug)

33. ACTIVE: ENERGY IS SUPPLIED TO DIFFUSANT Endocytosis or Transcytosis: Very large molecules are transported by invagination of the membrane and subsequent vesiculation and devesiculation Co-transport: Target molecule associates to another compound that crosses the cellular membrane due to the existing concentration gradient (this the case of glucose and aminoacids that associate to Na+ crossing the cellular membrane according to the concentration gradient). ATP pump: Energy required for molecules transport is supplied by the hydrolysis of high energy compounds such as ATP (ATP => ADP + P + energy). A typical example is represented by the Na+ - K+ pump.

34. 4 – CONTROLLED RELEASE SYSTEMS

35. MODELLI MATEMATICI MODELLI MATEMATICI MODELLI MATEMATICI MODELLI MATEMATICI SRC SISTEMA A RILASCIO CONTROLLATO PROGETTAZIONE AUMENTO DELLA PERFORMANCE (EFFICACIA TERAPEUTICA, COSTI)

36. PASSIVE PREPROGRAMMED 1 2 2 ACTIVE PREPROGRAMMED ACTIVE SELF PREPROGRAMMED CRS CATEGORIES

38. MICROFABRICATED MEMBRANE INSULIN 558 mm Na+, K+, Oxygen, Glucose ENCAPSULATED CELLS IMMUNOGLOBULINS MEMBRANE IMMUNOISOLANTI L. Leoni et al., Advanced Drug Delivery Review, 56 (2004) 211 RILASCIO DI INSULINA

39. S. Z. Razzacki et al., Advanced Drug Delivery Review, 56 (2004) 185