Rat Abdominal Wall Muscle
■ Immunoglobulin G (3 hours)
Small solute (1 hour)
0 200 400 600 800 1000
A Distance from Peritoeum (microns)
Figure 1 Distributed model concept of peritoneal transport in dialysis. Solutes in the blood transport across the wall of the capillaries distributed in the subperitoneal tissues. Solutes must follow a tortuous path through the interstitium, restricted by matrix molecules and by cells. The final barrier is the peritoneum, made up of a single layer of mesothelial cells and several layers of connective tissue. All solutes must pass across the peritoneum to the therapeutic solution in the cavity, which is replaced with fresh solution periodically to maintain the blood-to-peritoneal cavity concentration gradient that drives diffusion.
Careful dissection of the human intestinal peritoneum reveals six layers with a total thickness of somewhat less that 100 mm. The most superficial layer is the mesothelium, a continuous monolayer of cells that closely adhere to each other, which is a potential resistance to transport. Separating the mesothelial layer from the underlying connective tissue is a basement membrane. Under the basement membrane are networks of collagenous and elastic fibers. These five layers, making up the most superficial 30 to 40 mm, are devoid of blood and lymphatic vessels. The final layer is the deep latticed collagenous layer that ranges from 50 to 60 mm thick and contains most of the blood vessels of the anatomic peritoneum. The total thickness of the intestinal peritoneum of the human is 80 to 95 mm. Thus after passing the mesothe-lium, a solute transporting from the peritoneal cavity towards the blood must pass through 25 to 35 mm of tissue before reaching any blood vessels, which are scant in the deep collagenous layer. In the intestine, the layer of tissue under the peritoneum is the smooth muscle of the gut. There are at least 1,000 to 3,000 mm of muscle between the peritoneum and the extensive blood vasculature of the human intestinal villi. As discussed in the following section, the blood supply available to the cavity is chiefly from the smooth muscle of the gut.
The rat has been used as a model of peritoneal transport for more than 30 years, and the normal rat peritoneum resembles that of the human in many respects. Differences are that there is not a collagenous layer with blood vessels and that the peritoneum has a total thickness of 25 mm.
Figure 2 Solute concentration profiles measured by quantitative autoradiography in the abdominal wall of rats after 1 to 3 hours of dialysis with an isotonic solution containing either radiolabeled immunoglobulin G (MW = 150,000 Da) or a small solute (MW = 340 Da). Intraperitoneal pressure was 3 to 4 mmHg. The tissue concentrations have been normalized by the concentration in the original solution infused into the cavity. The degree of penetration of the profiles (0.5-0.6mm for small solutes and >1 mm for macromolecules) demonstrate that transperitoneal transport involves much more than the peritoneum itself.
Because the rat has very few blood vessels in the normal peritoneum, transport occurs between blood vessels in the parenchymal tissue below the peritoneum and the peritoneal cavity. Recent research has shown that the rat anatomic peritoneum has very little resistance to the passage of small solutes and macromolecules. Viral vectors, such as adenovirus, are the exception to this; they are completely absorbed into the mesothelial cell layer and do not pass beyond the normal anatomic peritoneum.
The Transport System Extends Well Beyond the Anatomic Peritoneum
The microcirculation of the underlying tissues is essential to transport of solutes and fluid between the peritoneal cavity and the circulating blood. The microcirculation of the anatomic peritoneum makes up only a small part of the microcirculation that is involved in transport of solute and water across the peritoneum. The blood supply to the mesentery exemplifies the microcirculation of the intrinsic peritoneum. The membranous-like structure of the mesentery with the sparse population of blood capillaries is a convenient means of study of the microvasculature, but it may not be representative of the microcirculation involved in transperitoneal exchange. Evidence for the amount of tissue involved with transport across the peritoneum is best obtained through the study of solute penetration into this tissue from the peritoneal cavity. Figure 2 demonstrates the degree of penetration of small solutes (MW = 200 to
5,000Da) and a larger molecule such as immunoglobulin G (IgG, MW = 150,000Da). In both of these experiments, a rat was dialyzed with large volume in the peritoneal cavity with a radiolabeled compound of mannitol or IgG. At 60 to 180 minutes after the introduction of the solution into the peritoneal cavity the animal was rapidly euthanized, the fluid was drained, and the tissue was rapidly frozen to preserve the concentration profile. Tissue was subsequently collected and analyzed with quantitative autoradiography. The profiles demonstrate that in the case of diffusion-dominated, small molecules (MW less than 5,000 Da), the penetration is on the order of 500 to 600 mm or approximately 1 mm. This is well beyond the thickness of the peritoneum, which in the rat is approximately 25 mm. On the other hand, the profile of a large molecule such as a protein, which is dominated by hydrostatic pressure-driven convection, demonstrates a much greater degree of penetration within the abdominal wall, because of tissue binding and relative lack of lymphatics that could remove the protein from the tissue. From this figure, it can be concluded that the tissue underlying the peritoneum that is involved with transport is a minimum of 0.5 to 1 mm thick and involves a significant amount of parenchymal tissue below the anatomic peritoneum.
Despite its continuous surface, there is an anatomical division of the peritoneum into the visceral portion, covering the intra-abdominal and pelvic organs, and the parietal peritoneum, which adheres to the retroperitoneal structures, the diaphragm, and the anterior abdominal wall. The abdominal aorta is the large vessel that passes through the diaphragm and supplies all of the abdominal tissues. The vena cava is the large vein to which all abdominal vessels ultimately drain. The visceral circulation supplies all of the internal organs including the liver, spleen, stomach, and intestines. The celiac artery divides into the splenic, left gastric, and hepatic arteries supplying respectively the spleen, stomach, and liver. Two other major vessels, the superior and inferior mesenteric arteries, form the arcade of vessels supplying the small and large intestines. Branches of the inferior mesenteric artery anastomose with branches of the superior mesenteric, which in turn anastomose with branches of the celiac. The venous drainage of the subperi-toneal tissues is a distinguishing feature of the visceral and parietal peritoneum. The veins that correspond to the arteries for these tissues combine to form the portal vein, through which blood is delivered first to the liver prior to reaching the vena cava. Therefore substances that transport into the blood from either the luminal side or the peritoneal side of the hollow organs will transit through the liver before reaching the central circulation and experience a "first-pass effect" of hepatic metabolism.
In contrast to the venous system draining the visceral tissues, blood from the parietal tissues drains directly into the vena cava. Separate arteries supply the kidneys and the ovaries, while their respective veins drain to the vena cava.
The right and left deep circumflex iliac arteries supply the sublumbar muscles of the abdominal wall, and at the level of the sacrum approach the skin. Five lumbar arteries branch from the abdominal aorta and supply the para-axial and lumbar muscles, the skin, and the spinal cord, while the epigastric arteries supply the remaining muscles of the abdominal wall. The veins corresponding to these arteries that supply the retroperitoneal tissue and the inferior abdominal wall are close to the arteries and essentially drain into the vena cava directly without going through the liver. The phrenic arteries supply the diaphragm, and the corresponding veins drain to the ipsilateral renal veins, which lead directly to the vena cava.
From a pharmacokinetic point of view, the important information to note from this discussion is that the parietal peritoneal circulation is separate from the visceral circulation and that the drainage from the parietal circulation does not transit through the liver before joining the general circulation. Thus substances that transport into the tissue of the diaphragm, lumbar muscles, or the anterior abdominal wall are transferred directly to the vena cava and to the central circulation without passing through the liver. On the other hand, substances that transport into the tissues of the gut, liver, spleen, and pancreas will transit through the liver prior to entering the central circulation. Figure 3 is a diagram of a
Figure 3 Multicompartment model of intraperitoneal drug delivery. The four tissue compartments result from the anatomy of the cavity and the blood and lymph drainage of the tissues. In the figure: Q, blood flow; L, lymph flow; S, solute transport; F, volume flow. Subscripts: AW, abdominal wall; D, diaphragm; HV, hollow viscera; L, liver; LA, liver artery; LV, liver vein; PV, portal vein; RLD, right lymph duct; TD, thoracic duct. (Data replotted from M. F. Flessner, Am. J. Physiol. 1985, Cancer Res. 1994.)
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