Phosphate intestinal absorption

Although it is being found that vitamin D metaboUtes play a role ia many different biological functions, metaboHsm primarily occurs to maintain the calcium homeostasis of the body. When calcium semm levels fall below the normal range, 1 a,25-dihydroxy-vitainin is made when calcium levels are at or above this level, 24,25-dihydroxycholecalciferol is made, and 1 a-hydroxylase activity is discontiaued. The calcium homeostasis mechanism iavolves a hypocalcemic stimulus, which iaduces the secretion of parathyroid hormone. This causes phosphate diuresis ia the kidney, which stimulates the 1 a-hydroxylase activity and causes the hydroxylation of 25-hydroxy-vitamin D to 1 a,25-dihydroxycholecalciferol. Parathyroid hormone and 1,25-dihydroxycholecalciferol act at the bone site cooperatively to stimulate calcium mobilization from the bone (see Hormones). Calcium blood levels are also iafluenced by the effects of the metaboUte on intestinal absorption and renal resorption. 

Vitamin D is a family of closely related molecules that prevent rickets, a childhood disease characterized by inadequate intestinal absorption and kidney reabsorption of calcium and phosphate. These inadequacies eventually lead to the demineralization of bones. The symptoms of rickets include bowlegs,... 

Human parathyroid hormone (hPTH) is an 84 amino acid polypeptide that functions as a primary regulator of calcium and phosphate metabolism in bones. It stimulates bone formation by osteoblasts, which display high-affinity cell surface receptors for the hormone. PTH also increases intestinal absorption of calcium. 

The example of amprenavir, an HIV-1 protease inhibitor, shows that intestinal metabolism can also be used as a strategy to enhance the bioavailability of compounds. In the biopharmaceutics classification system (BCS), amprenavir can be categorized as a class II compound it is poorly soluble but highly permeable [51]. Fosamprenavir, the water-soluble phosphate salt of amprenavir, on the other hand, shows poor transepithelial transport. However, after oral administration of fosamprenavir, this compound is metabolized into amprenavir in the intestinal lumen and in the enterocytes mainly by alkaline phosphatases, resulting in an increased intestinal absorption [51, 174],... 

Mechanism of Action A nonabsorbable compound that alters urinary composition of calcium, magnesium, phosphate, and oxalate. Calcium binds to cellulose sodium phosphate, thus preventing intestinal absorption of it. Therapeutic Effect Prevents the formation of kidney stones. 

Approximately two thirds of kidney stones contain Ca2+ phosphate or Ca2+ oxalate. Many patients with such stones exhibit a defect in proximal tubular Ca2+ reabsorption that causes hypercalciuria. This can be treated with thiazide diuretics, which enhance Ca2+ reabsorption in the distal convoluted tubule and thus reduce the urinary Ca2+ concentration. Salt intake must be reduced in this setting, since excess dietary NaCI will overwhelm the hypocalciuric effect of thiazides. Calcium stones may also be caused by increased intestinal absorption of Ca2+, or they may be idiopathic. In these situations, thiazides are also effective, but should be used as adjunctive therapy with other measures. 

Calcium and phosphate enter the body from the intestine. The average American diet provides 600-1000 mg of calcium per day, of which approximately 100-250 mg is absorbed. This figure represents net absorption, because both absorption (principally in the duodenum and upper jejunum) and secretion (principally in the ileum) occur. The amount of phosphorus in the American diet is about the same as that of calcium. However, the efficiency of absorption (principally in the jejunum) is greater, ranging from 70% to 90%, depending on intake. In the steady state, renal excretion of calcium and phosphate balances intestinal absorption. In general, over 98% of filtered calcium and 85% of filtered phosphate is reabsorbed by the kidney. The movement of calcium and phosphate across the intestinal and renal epithelia is closely regulated. Intrinsic disease of the intestine (eg, nontropical sprue) or kidney (eg, chronic renal failure) disrupts bone mineral homeostasis. 

Three hormones serve as the principal regulators of calcium and phosphate homeostasis parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and the steroid vitamin D (Figure 42-2). Vitamin D is a prohormone rather than a true hormone, because it must be further metabolized to gain biologic activity. PTH stimulates the production of the active metabolite of vitamin D, l,25(OH)2D. l,25(OH)2D, on the other hand, suppresses the production of PTH. l,25(OH)2D stimulates the intestinal absorption of calcium and phosphate. l,25(OH)2D and PTH promote both bone formation and resorption in part by stimulating the proliferation and differentiation of osteoblasts and osteoclasts. Both... 

Effect of vitamin D on the intestine 1,25-diOH D3 stimulates intestinal absorption of calcium and phosphate. 1,25-diOH D3 enters the intestinal cell and binds to a cytosolic receptor. The 1,25-diOH D3-receptor complex then moves to the nucleus where it selectively interacts with the cellular DNA. As a result, calcium uptake is enhanced by an increased synthesis of a specific calcium-binding protein. Thus, the mechanism of action of 1,25-diOH D3 is typical of steroid hormones (see p. 238). 

Vitamin D is a precursor for a number of compounds that increase intestinal absorption and decrease renal excretion of calcium and phosphate. Metabolites of vitamin D and their pharmacologic analogs are typically used to increase blood calcium and phosphate levels and to enhance bone mineralization in conditions such as osteodystrophy, rickets, or other situations where people lack adequate amounts of vitamin D. Vitamin D analogs such as calcitriol have also been combined with calcium supplements to help treat postmenopausal osteoporosis,4,9 and to treat bone loss caused by antiinflammatory steroids (glucocorticoids see Chapter 29 28.76 Specific vitamin D-related compounds and their clinical applications are listed in Table 31-5. 

Tissues contain two types of receptors for 1,25-dihydroxyvitamin D a classic steroid hormone nuclear receptor and a putative membrane receptor. 1,25-Dihydroxyvitamin D interacts with the nuclear receptor to form a receptor-ligand complex (Fig. 30-4). This complex then interacts with other nuclear proteins, such as the retinoic acid receptor (RXR) to form a functional transcription complex. The main effect of this transcription complex is to alter the amount of mRNAs coding for selected proteins such as cal-bindin, the calcium transport protein in the intestine, and the vitamin D receptor. In concert with PTH, 1,25-dihydroxyvitamin D acts to mobilize calcium from bone.As a consequence, serum calcium and phosphate homeostasis is maintained by a combination of 1,25-dihydroxyvitamin D stimulation of intestinal absorption and bone turnover. 

The relationship of serum calcium and phosphate with rickets was discovered by Howland and Kramer [10]. They found that blood from normal rats could mineralize rachitic rat cartilage, whereas blood from rachitic rats could not. They also provided evidence that a low serum calcium and phosphate status caused rickets. Orr etal. [11] demonstrated that UV irradiation stimulated calcium absorption. This study was largely unappreciated for 30 years until Nicolaysen and Eeg-Larsen [12] and Schachter and Rosen [13] demonstrated evidence for vitamin D-induced intestinal absorption of calcium by an active transport process. 

Vitamin B Three substances are classed under the term pyridoxine or adermine pyridoxol, pyridoxal and pyridoxamine. Pyridoxine was isolated by various study groups in 1938. Its structure was described by Folkers and Kuhn in 1939. Pyridoxal and pyridoxamine were discovered by Snell in 1942. Pyridoxal phosphate and pyridoxamine phosphate are biologically active substances. Intestinal absorption of Bg is dose-dependent and not limited. In alcoholism, a deficiency of vitamin Bg is encountered in 20—30% of cases, whereas the respective percentage is 50—70% in alcoholic cirrhosis. Vitamin Bg is an important coenzyme for transaminases, which transfer amino groups from amino adds to keto acids. In this way, biochemical pathways between the dtiic acid cycle and carbohydrate and amino acid metabolisms are created. (104)... 

SEDA-22, 172) (1,2). However, hypercalcemia has also been reported in a few patients using no more than the recommended doses (3,4). Calcipotriol exerts its effects on systemic calcium homeostasis by increasing intestinal absorption of calcium and probably phosphate. This results in suppression of parathyroid hormone and 1,25-dihydroxycolecalciferol (5). 

Bone contains nearly all of the calcium (99%), most of the phosphate (85%), and much of the magnesium (55%) of the body. The concentrations of calcium, phosphate, and magnesium in plasma are dependent on the net effect of bone mineral deposition and resorption, intestinal absorption, and renal excretion. PTH and 1,25-dihydroxyvitamin D are the principal hormones regulating these three processes. 

Hypophosphatemia or phosphate depletion may be caused by (1) a shift of phosphate from extracellular to intracellular spaces, (2) renal phosphate wasting, (3) decreased intestinal absorption, and (4) loss from intracellular phos-phate. Box 49-5 lists the commonly encountered causes of hypophosphatemia and phosphate depletion. 

In the kidneys, PTH (1) induces 25-hydroxyvitamin D-la-hydroxylase, increasing the production of l,25(OH)2D, which stimulates intestinal absorption of both calcium and phosphate, (2) increases calcium reabsorption in the distal convoluted tubule of the nephron, (3) decreases reabsorption of phosphate by the proximal tubule, and (4) inhibits Na -H antiporter activity, which favors a mild hyperchloremic metabolic acidosis in hyperparathyroid states. 

Drugs have also been associated with osteomalacia. Anticonvulsants increase the hepatic cataboHsm of vitamin D metabolites, and produce end-organ resistance. Phosphatebinding antacids used for treatment of peptic ulcer disease cause osteomalacia by preventing the intestinal absorption of phosphate. Etidronate treatment (e.g., of Paget s disease, osteoporosis, or hypercalcemia of mafignancy) can cause a mineralization defect and result in osteomalacia. 

Osteitis fibrosa (hyperparathyroid bone disease) is the most common high-turnover bone disease. This disorder is caused by the high concentrations of serum PTH in secondary hyperparathyroidism. Secondary hyperparathyroidism is a consequence of the hypocalcemia associated with hyperphosphatemia and l,25(OH)2D deficiency. Hyperphosphatemia is a result of the kidneys inability to excrete phosphate. l,25(OH)2D deficiency results from the inability of the kidneys to synthesize l,25(OH)2 because of decreased renal mass and suppression of 25(OH)D-la-hydroxylase activity by high concentrations of phosphate. Deficiency of l,25(OH)2D leads to reduced intestinal absorption of calcium and reduced inhibition of PTH secretion by l,25(OH)2D. Skeletal resistance to PTH also contributes to the hypocalcemia and secondary hyperparathyroidism. 

As intestinal absorption of calcium increases, urinary calcium excretion also increases. When the latter exceeds 300 mg/d, formation of calcium phosphate or calcium oxalate stones (urolithiasis) may occur. Hypercalciuria may result from decreased reabsorption of calcium due to a renal tubular defect or from increased intestinal absorption of calcium. Hypercalciuria may be due to an intrinsic defect in the intestinal mucosa or secondary to increased synthesis of 1,25-(OH)2D in the kidney. Disordered regulation of 1,25-(0H)2D synthesis is relatively common in idiopathic hypercalciuria. Treatment usually includes reduction in dietary calcium. Increased vitamin D intake, hyperparathyroidism, and other disorders can also cause hypercalciuria and urolithiasis. 

H)2D increases reabsorption of phosphate in the kidney and intestinal absorption of phosphate. In the intestine, phosphate is absorbed as a counterion with Ca + and also by a calcium-independent route. Phosphate flux through both pathways is increased by l,25-(OH)2D but more slowly than calcium transport. The calcium-independent pathway may involve alkaline phosphatase, the activity of which is increased by l,25-(OH)2D. In rat intestine in vitro, phosphate transport is greatest in the jejunum and least in the ileum, whereas calcium uptake is highest in the duodenum. 

Active transport mechanisms for the intestinal absorption of amino acids, oligopeptides, monosaccharides, monocarboxylic acids, phosphate, bile acids, and a number of vitamins have been identified and the review by Tsuji and Tamai provides an excellent summary of those mechanisms. The potential use of intestinal peptide and hepatic bile acid carriers to enhance drug absorption also has been reviewed. Structural and molecular modeling studies have postulated molecular structural features necessary for substrate recognition by the intestinal peptide carrier and the bile acid carrier. ... 

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