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5 – DETERMINATION OF INTESTINE PERMEABILITY 8

SINGLE PASS. RECIRCULATING. 5 – DETERMINATION OF INTESTINE PERMEABILITY 8. DRUG SOLUTION. In vivo (rat, human being) drug permeation through the intestinal mucosa mainly takes place according to a passive diffusive mechanism ( Transcellular route ) 9. 1. 2.

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5 – DETERMINATION OF INTESTINE PERMEABILITY 8

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  1. SINGLE PASS RECIRCULATING 5 – DETERMINATION OF INTESTINE PERMEABILITY8 DRUG SOLUTION

  2. In vivo (rat, human being) drug permeation through the intestinal mucosa mainly takes place according to a passive diffusive mechanism (Transcellular route)9 1 2 A little effect would be exerted by the aqueous stagnant layer arising at the intestinal wall9 5a – MODELING8

  3. Solute H2O

  4. QP>0 QP<0 RIN q(X) + dq(X) C(X) + dC(X) q(X) C(X) QI QU X X + dX CI CRI CU CRU L SINGLE PASS: MARKER INTEGRAL MASS BALANCE +

  5. QP>0 QP<0 RIN q(X) + dq(X) C(X) + dC(X) q(X) C(X) QI QU X X + dX CI CRI CU CRU L SINGLE PASS: DRUG DIFFERENTIAL MASS BALANCE STEADY STATE CONDITIONS

  6. ASSUMING: CORRECTING FACTOR CF

  7. L qi Ci qo Co Inlet connector Outlet connector Intestine L1 R1 L2 R2 qw< 0 qw> 0 Pump RESERVOIR (Cr = mr/Vr) RECIRCULATING TECHNIQUE LINEAR VARIATION OF ABSORBED/DESORBED WATER VOLUME

  8. Intestine x q C x+dx q+dq C+dC qw< 0 qw> 0

  9. Ci is now time dependent it represents drug concentration in the reservoir fluid at time t – t1, t1 = time required to solution to pass from the reservoir to the intestinal beginning and it can be defined by

  10. Conventionally, time t = 0 corresponds to the completion of the first loop by solution (for t <0, Cr = Cr0). At this time, the reservoir solution volume Vri will be: Vri = Vsi – V1 – Vint + qw (tint + t2) – V2 FOR t > 0 Vr = Vri + qwt

  11. INTESTINE INTESTINE RESERVOIR MATHEMATICAL MODEL:t < t1 + t2 + tint

  12. INTESTINE INTESTINE RESERVOIR MATHEMATICAL MODEL:t>t1 + t2 + tint

  13. 6 - CASE STUDY MARKER: PHENOL RED DRUG: ANTIPYRINE RAT: MALE WISTAR WEIGHT: 300 – 350 g FASTED for 16 h (water ad limitum) prior to each experiment ANAESTHESIAinduced with i.m.injection of Ethyl Urethane dissolved in physiological solution (1.5 g/Kg). To maintain normal body temperature rats were placed on a heated slide (37°C). The abdomen was opened with a midline longitudinal incision and a jejunal segment of approximately 30 cm was measured and cannulated with a plastic tubing (outlet and inlet tubes diameter equal to 0.4 cm) inserting the outlet tube at 30 cm far from the cecal intestine. Put the intestinal tract in its anatomical position so that the inlet and outlet tubes are out of the abdomen, the surgical area was covered with a cotton sheet constantly wetted by means of a 37°C physiological solution.

  14. SINGLE PASS EXPERIMENT (R = 0.173 cm)

  15. SINGLE PASS: PERMEABILITY EVALUATION

  16. RECIRCULATING EXPERIMENT (R = 0.173 cm)

  17. RECIRCULATING: PERMEABILITY EVALUATION P = (2.3 ± 1.1)*10-3 cm/min single pass

  18. MODEL BEST FITTING

  19. CORRECTING FACTOR: H2O ABSORPTION H2O DESORPTION

  20. 7 – REFERENCES • Colorado State University, Biomedical Hypertextbooks, Digestion, Small Intestine. http://www.vivo.colostate.edu/hbooks/pathphys/digestion/smallgut/ • Toner, P. G.; Karr, K. E., Scientific foundations of gastroenterology, Sircus, W.; Smith, A. N.; Eds., W. B. Saunders, Philadelphia, 1980 • Singer S J, Nicolson G L. The fluid mosaic model of the structure of cell membranes. Science 1972, 175, 720-731. • Camenish G, Folkers G, Waterbeemd van de H, Review of theoretical passive drug absorption models: Historical backgroung, recent developments and limitations. Pharm. Acta Helv. 71, 1996, 309-327 • Pappenheimer J R, Reiss K Z. Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat. J. Membr. Biol. 1987, 100, 123-136 • Naasani I, Sugawara M, Kobayashi M, Iseki K, Miyazaki K. Transport mechanism of ceftibuten, a dianionic cepherm, in rat renal brush-border membrane. Pharm. Res. 1995, 12, 605-608 • Carr, K. E.; Toner, P. G.; Morphology of the intestinal mucosa, Pharmacology of the intestinal permeation I, Cap. 1, ;Csaky, T. Z.; Ed., Springer-Verlag, Berlin, 1984.

  21. M. Grassi, G. Cadelli, Theoretical considerations on the in vivo intestinal permeability determination by means of the single pass and recirculating techniques, Int. J. Pharm. 2001, 229, 95-105. • Fagerholm, U., Lennernäs, H. Experimental estimation of the effective unstirried water layer thickness in the human jejunum, and its importance in oral drug absorption. Eur. J. Pharm. Sci. 1995, 3, 247-253.

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