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    Pathway of P.O. Absorption

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    Describe in detail the pathway of p.o. absorption including primary site of absorption, entry into the circulatory system, pathway to the liver, and first pass effect. Also include the types of enzymes and their function in the gut and liver. References please.

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    1. Site of absorption

    After oral administration, drug absorption occurs predominantly within the small intestine, because of the large surface area provided by epithelial folding and the villous structures of the absorptive cells. In humans, the mucosa of the small intestine has a large surface area which is increased greatly by the folds of Kercking, villi, and microvilli and is approximately 200 m2 in adults (Wilson and Washington, 1989). Drug absorption across the gut wall can be mediated by either transcellular or paracellular transport, or a combination of both.

    2. Entry into the circulatory system

    For transcellular transport, drugs are transported into and through the epithelial cells, and then into the blood circulation, whereas for paracellular transport, drugs reach the blood circulation via the tight junctions between epithelial cells. The relative contribution of the transcellular and paracellular pathway to overall absorption is highly dependent on the lipophilicity of drugs. In vitro studies with Caco-2 cells revealed that the relative contribution of the transcellular pathway was 25%, 45%, 85%, and 99% for chlorothiazide, furosemide, cimetidine, and propranolol, respectively. These values correlated well with the lipophilicity of the compounds in question, the log P values of which were.2,.08, .4, and 3.6, respectively (Pade and Stavchansky, 1997). From these data, it is clear that the uptake of drug into epithelial cells is not obligatory during absorption. Obviously, only those drugs that are absorbed via the transcellular, but not the paracellular, pathway are subject to intestinal first-pass metabolism.

    3. Pathway to the liver - first pass effect.

    Anatomically, the small intestine has a serial relationship with the liver relative to the absorption and is the anterior organ. However, the primary function of the small intestine is to absorb nutrients and water. This is achieved by mixing food with digestive enzymes to increase the contact of foodstuffs with the absorptive cells of the mucosa. In humans, the small intestine is about 5 to 6 m in length and comprises approximately 1% of body weight (ca. 0.7 kg for adults), which is significantly smaller than the liver (ca. 1.5 kg for adults). Approximately 6 to 12 liters of partially digested foodstuffs, water, and secretions are delivered daily to the small intestine. Of this, only 10 to 20% are passed on to the colon, because most nutrients, electrolytes, and water are absorbed as they are transported through the small intestine. Absorption and movement of the contents are brought about by the activities of the absorptive cells of the mucosa and by coordinated contraction of the smooth muscle cells of the muscularis extern (Weisbradt, 1987; Guyton, 1991). In addition to this fundamental role, a secondary function of the small intestine arises from the fact that it is also a major route of entry into the body for many xenobiotics including drugs.
    Although the small intestine is regarded as an absorptive organ in the uptake of orally administered drugs, it also has the ability to metabolize drugs by numerous pathways involving both phase 1 and phase 2 reactions. Anatomically, the small intestine has a serial relationship with the liver relative to the absorption and is the anterior organ. The amount of an orally administered drug that reaches the systemic circulation can be reduced by both intestinal and hepatic metabolism. The metabolism of drugs before entering the systemic circulation is referred to as first-pass metabolism. It has been widely believed that the liver is the major site of such first-pass metabolism because of its size and its high content of drug-metabolizing enzymes.
    Recent clinical studies, however, have indicated that the small intestine contributes substantially to the overall first-pass metabolism of cyclosporine, nifedipine, midazolam, verapamil, and certain other drugs. Some studies have even suggested that the role of intestinal metabolism is quantitatively greater than that of hepatic metabolism in the overall first-pass effect (Wu et al., 1995; Holtbecker et al., 1996; Fromm et al., 1996).
    Much of the evidence for such claims has derived indirectly from comparisons of areas under the plasma concentration curves (AUCs)2 after i.v. and oral administration, with assumptions that have not yet been tested. In fact, estimates of intestinal metabolism calculated by indirect methods often contradicted those determined from direct measurements. For example, nifedipine, a well absorbed drug, is subject to substantial first-pass metabolism which results in an oral bioavailability of about 30 to 50%. Using an indirect method, Holtbecker et al. (1996) concluded that the contribution of intestinal metabolism was quantitatively as important as that of hepatic metabolism to the overall first-pass metabolism of nifedipine in humans.
    However, Breimer and his coworkers (Kleinbloesem et al., 1986) have demonstrated that the intestinal metabolism of nifedipine in patients with a portalcaval shunt was absent, because the bioavailability of nifedipine in these patients was complete (100%). In these patients, the portal blood circulation bypassed the liver. Similarly, inconsistencies were noted between the direct and indirect estimation of intestinal metabolism for verapamil in humans (Eichelbaum et al., 1980; Fromm et al., 1996). These findings, therefore, raise the question as to whether intestinal metabolism truly plays such an important role in the first-pass effect, or whether the role of intestinal metabolism is overemphasized (Lin et al., 1997). (article referenced at the end of the article below).
    Enzymes in Gut (Small Intestines)and Liver
    B. Localization of Drug-Metabolizing Enzymes in the Small Intestine
    1. Cytochromes P-450 (see p. 6 below)
    2. UDP Glucosyltransferases and Sulfotransferases (p. 8)

    C. Intestinal Enzyme Induction
    1. Cytochromes P-450 (p. 10 below)
    2. UDP Glucosyltransferases (p. 10 below)
    3. Effect of Route and Dose on Enzyme Induction (p. 11 below)

    For more details on the role of the specific enzymes visit full article http://pharmrev.aspetjournals.org/cgi/content/full/51/2/135#SEC2_10- or go to pages listed in the full article at the end whichever is easier).
    D. p-Glycoprotein

    1. Intestinal p-glycoprotein (p. 13 below) - For example, Immunohistological studies with human small intestine indicated that p-glycoprotein is located on the apical brush border membrane of the mature epithelium (Thiebaut et al., 1987 ). Therefore, p-glycoprotein may play a role in limiting the absorption of p.o. administered drugs by extruding the drugs from the epithelial cells into the intestinal lumen. (P. 13 BELOW)
    2. Cytochromes P-450 and p-Glycoprotein (P. 13 below)- As described above, both cytochromes P-450 and p-glycoprotein function to protect the body from toxic accumulation of hydrophobic xenobiotics via metabolism and excretion.
    3. p-Glycoprotein and Intracellular Residence Time (p. 14 below) - Because of its anatomical location, p-glycoprotein can act as a countertransporter that extrudes foreign compounds from inside the enterocytes into the intestinal lumen as they begin to be absorbed across the epithelial cells. A portion of the extruded xenobiotics then can be reabsorbed into the enterocytes. Thus, it is possible that p-glycoprotein increases the exposure of drugs to drug-metabolizing enzymes and hence enhances intestinal metabolism of drugs by prolonging their intracellular residence time through the repetitive process of extrusion and reabsorption.

    Drug Absorption and Intestinal First-Pass Metabolism (p. 15 below)
    Regardless of whether the transcellular or paracellular pathway operates, absorption rates of most drugs can be described by Fick's law of simple diffusion. The rate (amount) of drug absorbed is determined by the coefficient of diffusion, the surface are of the mucosa, and the concentration gradient of the drug (Macey, 1978 ). The concentration gradient across the unstirred water layer and epithelial plasma membrane leads to reduced drug concentration in the enterocytes. The magnitude of the lumen-enterocyte concentration gradient is dependent on the drug's lipophilicity and the thickness of the unstirred water layer (Ho et al., 1983 ). Drug in the intracellular space will continue to diffuse along a concentration gradient into capillary blood, and the mucosal capillary blood drains into the mesenteric veins which converge to form the hepatic partial vein. In addition to the mucosal blood flow, there is significant contribution from the splanchnic area, such as the splenic vein and gateric vein, to the portal blood flow. Again, this leads to reduced drug concentration in the portal vein before entering the liver.
    The drug concentration in the portal vein will be diluted further by intimate mixing with hepatic arterial blood before it passes evenly through the hepatocytes. Because of the mixing and dilution effects, the drug concentration in hepatocytes would be significantly lower than that in enterocytes. As will be discussed in the next section, the rate of biotransformation and the intrinsic clearance are concentration-dependent parameters. The higher the drug concentration the lower its intrinsic clearance will be. This means that saturable metabolism would be more likely to occur in the intestine than in the liver during drug absorption. Thus, the extent of intestinal first-pass metabolism is highly dependent on the oral dose. At high dose of a given drug, intestinal first-pass metabolism is expected to be appreciably less than following low doses of the same agent. (see p. 19 below for more detail).
    B. Saturable First-Pass Metabolism (p. 16 below)
    C. Hepatic and Intestinal Organ Clearance
    (full article at http://pharmrev.aspetjournals.org/cgi/content/full/51/2/135#SEC2_10)
    FINAL COMMENTS I HOPE THIS HELPS AND TAKE CARE.

    Vol. 51, Issue 2, 135-158, June 1999
    Is the Role of the Small Intestine in First-Pass Metabolism Overemphasized?
    Jiunn H. Lin1, Masato Chiba and Thomas A. Baillie
    (http://pharmrev.aspetjournals.org/cgi/content/full/51/2/135#SEC2_10)
    Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania
    I. Introduction
    II. Physiological and Biochemical Factors Affecting Intestinal Metabolism
    A. Anatomy and Circulation of the Small Intestine
    1. Mucosal Blood Flow
    2. Countercurrent Exchange
    B. Localization of Drug-Metabolizing Enzymes in the Small Intestine
    1. Cytochromes P-450
    2. UDP Glucosyltransferases and Sulfotransferases
    C. Intestinal Enzyme Induction
    1. Cytochromes P-450
    2. UDP Glucosyltransferases
    3. Effect of Route and Dose on Enzyme Induction
    D. p-Glycoprotein
    1. Intestinal p-Glycoprotein
    2. Cytochromes P-450 and p-Glycoprotein
    3. p-Glycoprotein and Intracellular Residence Time
    III. Drug Absorption and Intestinal First-Pass Metabolism
    A. Drug Absorption and Concentration Gradient
    B. Saturable First-Pass Metabolism
    C. Hepatic and Intestinal Organ Clearance
    IV. Relative Contribution of Hepatic and Intestinal First-Pass Metabolism
    V. Conceptions and Misconceptions
    VI. Conclusions
    Acknowledgments
    References
    I. Introduction
    The primary function of the small intestine is to absorb nutrients and water. This is achieved by mixing food with digestive enzymes to increase the contact of foodstuffs with the absorptive cells of the mucosa. In humans, the small intestine is about 5 to 6 m in length and comprises approximately 1% of body weight (ca. 0.7 kg for adults), which is significantly smaller than the liver (ca. 1.5 kg for adults). Approximately 6 to 12 liters of partially digested foodstuffs, water, and secretions are delivered daily to the small intestine. Of this, only 10 to 20% are passed on to the colon, because most nutrients, electrolytes, and water are absorbed as they are transported through the small intestine. Absorption and movement of the contents are brought about by the activities of the absorptive cells of the mucosa and by coordinated contraction of the smooth muscle cells of the muscularis extern (Weisbradt, 1987 ; Guyton, 1991 ). In addition to this fundamental role, a secondary function of the small intestine arises from the fact that it is also a major route of entry into the body for many xenobiotics including drugs.
    Although the small intestine is regarded as an absorptive organ in the uptake of orally administered drugs, it also has the ability to metabolize drugs by numerous pathways involving both phase 1 and phase 2 reactions (Caldwell and Marsh, 1982 ; Renwick and George, 1989 ; Ilett, 1990 ; Ilett et al., 1990 ; Krishna and Klotz, 1994 ). Anatomically, the small intestine has a serial relationship with the liver relative to the absorption and is the anterior organ. The amount of an orally administered drug that reaches the systemic circulation can be reduced by both intestinal and hepatic metabolism. The metabolism of drugs before entering the systemic circulation is referred to as first-pass metabolism. It has been widely believed that the liver is the major site of such first-pass metabolism because of its size and its high content of drug-metabolizing enzymes.
    Recent clinical studies, however, have indicated that the small intestine contributes substantially to the overall first-pass metabolism of cyclosporine, nifedipine, midazolam, verapamil, and certain other drugs (Hebert et al., 1992 ; Wu et al., 1995 ; Paine et al., 1996 ; Holtbecker et al., 1996 ; Fromm et al., 1996 ). Some studies have even suggested that the role of intestinal metabolism is quantitatively greater than that of hepatic metabolism in the overall first-pass effect (Wu et al., 1995 ; Holtbecker et al., 1996 ; Fromm et al., 1996 ). Much of the evidence for such claims has derived indirectly from comparisons of areas under the plasma concentration curves (AUCs)2 after i.v. and oral administration, with assumptions that have not yet been tested. In fact, estimates of intestinal metabolism calculated by indirect methods often contradicted those determined from direct measurements. For example, nifedipine, a well absorbed drug, is subject to substantial first-pass metabolism which results in an oral bioavailability of about 30 to 50%. Using an indirect method, Holtbecker et al. (1996) concluded that the contribution of intestinal metabolism was quantitatively as important as that of hepatic metabolism to the overall first-pass metabolism of nifedipine in humans. However, Breimer and his coworkers (Kleinbloesem et al., 1986 ) have demonstrated that the intestinal metabolism of nifedipine in patients with a portalcaval shunt was absent, because the bioavailability of nifedipine in these patients was complete (100%). In these patients, the portal blood circulation bypassed the liver. Similarly, inconsistencies were noted between the direct and indirect estimation of intestinal metabolism for verapamil in humans (Eichelbaum et al., 1980 ; Fromm et al., 1996 ). These findings, therefore, raise the question as to whether intestinal metabolism truly plays such an important role in the first-pass effect, or whether the role of intestinal metabolism is overemphasized (Lin et al., 1997 ).
    The purpose of this review was to examine carefully the physiological, biochemical, and pharmacokinetic factors that influence the extent of intestinal metabolism, with an attempt to address its true importance in first-pass metabolism.
    II. Physiological and Biochemical Factors Affecting Intestinal Metabolism
    A. Anatomy and Circulation of the Small Intestine
    The small intestine is divided arbitrarily into three parts: duodenum, jejunum, and ileum. These regions are not anatomically distinct, although there are differences in their absorptive and secretory capabilities. In humans, the duodenum is the shortest, widest, and least mobile section. It measures 20 to 30 cm in length and 3 to 5 cm in diameter. The rest of the small intestine is about 5-m long; the proximal two-fifths is referred to as the jejunum and the distal three-fifths is called the ileum. The wall of the jejunum is thicker and its lumen is wider than that of the ileum. In general, there is a gradual ...

    Solution Summary

    This solution describes in detail the pathway of p.o. absorption. including primary site of absorption, entry into the circulatory system, pathway to the liver, and first pass effect. It also includes the types of enzymes and their function in the gut and liver. References provided.

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