Properties of GI tract, pH partition hypothesis

Properties of GI tract, permeability solubility charge state, pH partition hypothesis, micro climate,tight junction complex , transport model.
Advanced biopharmaceutics and pharmacokinetics syallabus.
Mpharm 2bd sem syllabus

1. D rug absorption Presented by: Pallerla Naveen Reddy Mpharm(pharmaceutics), Central university of South Bihar.

2. Contents : Properties of GI Tract Permeation-solubility-charge state pH partition hypothesis Microclimate Tight junction complex

3. PHYSIOLOGICAL ASPECTS / PROPERTIES OF GI TRACT 1)GASTRIC EMPTYING : *Few drugs are absorbed from the stomach. *Most of the drugs are retained in stomach temporarily,largely in solution, and are progressively delivered to the small intestine where they are absorbed.*For this reason gastric emptying is a critical factor in drug absorption. *The emptying time of stomach through the pylorus is proportional to the volume remaining in thestomach. *This constitutes a first order process which can be characterized by a single half-life value. * The diferent type of food shows different values of gastric emptying time. The order ofgastric emptying can be summarized as follows. Carbohydrates < Proteins< Water< Lipids Example: paracetamol absorption is rate limited due to gastric emptying.

4. 2)Intestinal transit time: * The intestinal transit rate also has a significant influence on the drug absorption, since it determines the residence time of the drug in the absorption site. *I ncreasing the rate of gastric emptying and gastro-intestinal motility increases the rate of absorption of a drug but, for digoxin and riboflavin, increased gastrointestinal motility is associated with a decrease in the rate of absorption. *Since, intestine is the major site of absorption of most of the drugs, Long intestinal transit time is desirable for the complete absorptionof drugs.Delayed intestinal transit is desirable for: *Drugs that dissolve only in intestine (enteric coated) *Drugs absorbed from specific sites in the intestine.

5. Other factors: *GI motility *GI pH *Drug stability in GIT *Surface area *Blood flow to GIT

6. 3)WATER FLUXES IN THE GI TRACT: * In addition to the transport of material through the GI tract, water fluxes due to secretion and reabsorption in the different segments may significantly influence drug absorption. *Over a 24 hour period approximately the flow rate into the duodenum reaches between 6-10 liter of fluid perday. *Most of this fluid is reabsorbed in the duodenum so that at its distal end the flow rate is reduced to 3-5 liter per 24 hour. It is further reduced to 1.5-2 liter/24 hour by the end of thejejunum, 0.7-1.2 liter/24 hour by the end of the ileum, and is only 0.1 liter/24 hour at the end of the colon, i.e. in the faeces. *Water crosses the mucosal membrane through pores that are too smallfor transfer of drug molecules accross. *Water fluxes in the gut wall therefore are unlikely to have a direct effect on drug absorption. However, the presence of large volumes of water in the duodenum,and to a lesser extent in the jejunum and ileum, may influence the dissolutionof sparingly solubledrugs. The considerable water flux in these GI segments may also facilitate intra luminal transportof dissolved drug molecules towards the absorption sites on the mucosa. *The secretion andreabsorption of water also modifies the luminal concentration of drug and therefore its rate of absorption.

7. Permeability-Solubility-Charge State: *According to Ficks first law , passive diffusion of a solute is the product of diffusivity and concentration gradient of the solute inside the membrane. *The membrane/water apparent partition coefficient relates the latter internal gradient to the external bulk- water concentration difference between the two solutions separated by the membrane. *For an ionizable molecule to permeate by passive diffusion
most efficiently, the molecule needs to be in its uncharged form at the membrane surface.
*The amount of the uncharged form present at a given pH, which directly contributes to the flux, depends on several important factors, such as pH, binding to protein and bile acids, self-binding, and solubility.

8. PH PARTITION HYPOTHESIS *pH - partition theory explains the process of drug absorption from the GIT and its distribution across all biological membranes. *pH-partition theory states that for drug compounds of molecular weight more than 100, which are primarily transported across the bio membrane by passive diffusion, the process of absorption is governed by * Dissociation constant pKa of drug. * The lipid solubility of the unionized drug * pH at the absorption site As most of the drugs are weak electrolytes, their degree of ionization depends upon the pH of the biological fluid.

9. * This theory depends on some assumptions are as follows:- i) The GIT is simple lipoidal barrier for transport of drug. ii) Larger the fraction of unionized drug, faster the absorption ii) Greater the lipophilicity of unionized drug, better the absorption. a ) Pka of drug :- Amount of drug that exist in unionized form and in ionized form is a function of pKa of drug & pH of the fluid at the absorption site and it can be determined by Henderson- hesselbach equation: * pH = pKa + log [ lionized form / unionised form ]………. For, weakly acidic drugs

10. pH = pKa +( log unionized form/ionized form )…….. For , Weakly basic drugs. * When conditions reaches to the equilibrium the second term of both equations become zero (as log1 is equal to zero). Now pH becomes equal to pKa which is the characteristic feature of the drug. * The GIT has range of pH from 1 to 8, i.e. stomach has pH around 1-3 and intestine from 5-8. So on the basis of pH partition hypothesis some generalizations can be made for absorption of drugs. For Weak acidic drug:- i ) Very weak acids ( pKa > 8) such as phenytoin, ethosuximide are remain unionized at all pH values and therefore their absorption is rapid and independent of GI pH.

11. ii) Acids in the pKa range 2.5 to 7 .5 are greatly affected by changes in pH and therefore their absorption is pH-dependent; e.g. several NSAI D s like aspirin, ibuprofen, phenylbutazone, and a number of penicillin analogs. Such drugs are better absorbed from acidic conditions of stomach. iii)Stronger acids with pKa < 2.5 such as cromolyn sodium are ionized in the entire pH range of GIT and therefore remain poorly absorbed. For Basic drugs: i) Very weak bases i (pKa< 5) such as caffeine, diazepam etc are remain non ionized at all the ph values therefore their absorption is rapid and pH independent. ii)Bases in the pKa range 5 to 11.0 are greatly affected by changes in pH and hence their absorption is pH-dependent; e.g. Several morphine analogs, chloroquine, imipramine and amitriptyline. Such drugs are better absorbed from the relatively alkaline conditions of the intestine

12. Lipophilicity and Drug Absorption * As mentioned earlier, it is the pKa of a drug that dete rm ines the degree of ionization at a particular pH and that only the unionized drug, if sufficiently lipid soluble, is absorbed into the systemic circulation. * Thus, even if ithe drug exists in the unionized form , it will be poorly absorbed if it has poor lipid solubility (or low Ko / w). * Ideally, for optimum absorption, drug should have sufficient aqueous solubility to dissolve in the fluids at the absorption site and lipid solubility (Ko / w) hi gh e nough to facilitate the partitioning of the drug in the lipoidal biomembrane and into the systemic circulation. * In other words, a perfect hydrophilic -lipophilic balance (HLB) should be there in the structure of the drug for opti mum bioavailability.

13. *The lipid solubility of a drug is determined from its oil/water partition coefficient (K0/w) value. *This value is a measure of the degree of distribution of drug between one of the several organic, water immiscible,
lipophilic solvents such as n-octanol, etc. and an aqueous phase. *In general, the octanol/pH 7.4, buffer partition coefficient value in the range of I to 2 of a drug is sufficient for passive absorption across lipoidal membranes. *In yet another study by Schanker on a series of barbituric acid derivatives having .same pKa, the percent absorbed increased with an increase in the partition coefficient of the drug. *Thus, to enhance the bioavailability of a drug, not only its dissolution rate but also its rate of permeability should be considered

14. Limitations of pH partition hypothesis i ) The pH-partition theory provides a basic frame work for understanding drug absorption, but it is an over simplification of a more complex process ii) The theory indicates that the relationship between pH and permeation or absorption rate are described by an S- shaped curve corresponding to the dissociation curve of the drug. iii) For a simple acid or base, the inflection point of the pH- absorption curve should occur at a pHequal to the pka of the drug.

15. pH-absorption curve for acidic and basic drugs. Dotted lines indicate curves predicted by p H -partition hypot h esis And bold lines indicate that practical curves.

16. iv ) In general pH absorption curves are less steep then expected and are shifted to higher pH values for acids and to lower pH values for bases . I. Presence of virtual membrane pH
2. Absorption of ionized drug
3. Influence of GI surface area and residence time of drug
4. Presence of aqueous unstirred diffusion layer The experimental pH-absorption curves are less steep and shift to the left (lower pH values) for a basic drug and to the right (higher pH values) for an acidic drug. This led to the suggestion that a virtual pH, also called as the microclimate pH, different from the lumenal pH exists at the membrane surface. * The absorption of short-chain weak acids in the rat intestine, as a function of pH, appears not to confirm to the pH-partition hypothesis Ph MICROCLIMATE

17. *Similar anomalies were found with weak bases.
* The apparent pKa values observed in the absorption pH curve were shifted to higher values for acid sand to lower values for bases, compared with the true pKa values. * Such deviations could be explained by the effect of an acid layer on the apical side of cells, the so-called acid Ph microclimate. * Shiau et al directly measured the microclimate pH, pHm , to be 5.2 -6.7 in different sections of the intestine (very reproducible values in a given segment) covered with the normal mucus layer, as the luminal (bulk) pH, pHb , was kept at 7.2. *Good controls ruled out pH electrode artifacts. With the mucus layer washed off, pHm rise from 5.4 to 7.2. Values of pHb as low as 3 and as high as 10 remarkably did not affect values of pHm . * Glucose did not affect pHm when the microclimate was established .

18. *However, when the mucus layer had been washed off and pHm Was allowed to rise to pHb, the addition of 28 mM glucose caused the original low pHm to be reestablished after 5 min. * Shiau et al hypothesized that the mucus layer was an ampholyte (of considerable pH buffer capacity) which created the pH acid microclimate. *Said et al measured pHm in rat intestine under in vitro and in vivo conditions. As pH b was kept constant at 7 . 4, pHm values varied 6 . 4 - 6.3 (proximal to distal duodenum), 6.0 - 6.4 (proximal to distal Je j unum ), 6.6- 6.9 (proximal to distal ileum), and was 6.9 in the colon. * Serosal surface had normal ph . When glucose or sodium was removed from the bathing solutions, the pH m values began to ri se . Metabolic inhibitors (1 m Miodoacetate or 2 , 4- dinitrophenol) also caused the pHm values to rise.

19. *Said et al hypothesized that a Na+ /H+ antiporter mechanism, dependent metabolism, was responsible for the acid pH microclimate. * The tips of villi have the lowest phm values the secretion , whereas the crypt regions have pHm >8 values . * Most remarkable was that microclimate ( pHm 8) was observed in the human stomach, whose bulk p h b is generally about 1.7. *In the stomach and duodenum, the near- neutral microclimate pH Was attritbuted to the secretio of HCO3 from the epithelium.

20. TIGHT J UN C TION COMPLEX *Many structural components of the tight junctions (TJ) have been defined in the last ten years. Lutz and Siahaan reviewed the protein structural components of the (TJ). The occludin protein complex that makes the water pores so restrictive. *Freeze-fracture electron micrographs of the constrictive region of the TJ show netlike arrays of strands (made partly out the cytoskeleton. ) Circumscribing the cell, forming a division between the apical and the basolateral sides. *A region ten strands wide forms junctions that have very small pore openings ; fewer strands produce leakier junctions. The actual cell-cell adhesions occur in the adhesions junctions, located further away from the apical side.

21. * Apparently three calcium continuously link 10-residue portions cadherin proteins spanning from two adjoining cell walls. Calcium-binding agents can open the junctions by interactions with the cadherin complex.

22. References: *Biopharmaceutics and pharmacokinetics, authors-Dr.M.Brahmankar and Sunil B. Jaiswal, published on May 15,1995. From page number -6-51. *Juornal of physiology November- 1987,Factors affecting the microclimate pH in rat jejunum by T Shimada. *Fundamentals of biopharmaceutics and pharmacokinetics by V.Venkateswarlu Page no -25. *Molecular Pathophysiology of Epithelial Barrier Dysfunction in Inflammatory Bowel Diseases – Scientific Figure on ResearchGate. [accessed 13 May, 2022]

23. Thank you