Calcium complexing with tetracyclines

The calcium in food can complex with tetracycline to reduce its absorption. This is particularly notable with dairy products, which can reduce the absorption of the tetracyclines by up to 80%, thereby reducing or even abolishing their therapeutic effects. Doxyeyeline and minocycline are less affected by daily products (25 to 30% reduction). Orange juice and coffee do not interact with tetracycline. 

There are problems as well in the absorption of certain drugs in the presence of specific food components. L-Dopa absorption may be inhibited in the presence of certain amino acids formed from the digestion of proteins [43], The absorption of tetracycline is reduced by calcium salts present in dairy foods and by several other cations, including magnesium and aluminum [115-117], which are often present in antacid preparations. In addition, iron and zinc have been shown to reduce tetracycline absorption [118], Figure 17 illustrates several of these interactions. These cations react with tetracycline to form a water-in-soluble and nonabsorbable complex. Obviously, these offending materials should not be co-administered with tetracycline antibiotics. 

The sorption behaviour of antibiotics, in particular, can be very complex and therefore difficult to assess. As an example, ciprofloxacin has a log ATqw equal to 0.28, conferring it with a small tendency to leave the aquatic phase however, it does sorb well onto active sludge or sediments [62, 63] in WWTP. Tetracyclines (log A ow equal to 1.4), on the other hand, form complexes with double cations (calcium and magnesium) present in the water [64] and also tend to adsorb onto the surface of complexes between humic acids and hydrous Al oxide [65]. 

Gastrointestinal distress (nausea, vomiting, diarrhea) may be a problem with tetracycline use. Hypersensitivity reactions (such as rashes) may also occur, as well as an increase in skin sensitivity to ultraviolet light (photosensitivity).16 Tetracyclines form chemical complexes with calcium that may impair the growth and development of calcified tissues such as bone and teeth, especially in children.69 Tetracyclines also cause discoloration of teeth in children and pregnant women, apparently because of the tetracycline-calcium interaction.69 As mentioned previously, development of tetracycline-resistant strains and resulting superinfections may be a serious problem during tetracycline therapy. 

Because there is such a wide selection available, rational choice of the necessary excipients and their concentration is required. Consideration must also be given to cost, reliability, availability, and international acceptability. Although generally considered inert, formulation incompatibility of excipients is also necessary. Lactose, for example, can react with primary and secondary amines via its aldehyde group by Maillaird condensation reaction [6], and calcium carbonate is incompatible with acids due to acid-base chemical reaction and with tetracyclines due to complexation. Additionally, excipients can contribute to the instability of the active substance through moisture distribution. 

The administration of tetracycline with food can ameliorate its irritative effects, bnt food can adversely affect the drug s absorption. In contrast, the absorption of doxycycline is only slightly affected by the presence of food, including dairy prodncts. Becanse all tetracyclines can form complexes with divalent cations, the absorption of any tetracycline is markedly decreased when administered with iron-containing tonics or antacids containing calcium, magnesium, or aluminum. Sodium bicarbonate also adversely affects tetracycline absorption. 

Excipients may interact directly with the drug to form a water-soluble or water-insoluble complex. If tetracycline is formulated with calcium carbonate, an insoluble complex of calcium tetracycline is formed that has a slow rate of dissolution and poor absorption. 

Staining of permanent teeth by tetracyclines takes place during tooth development by well-documented mechanisms. Tetracycline forms a complex with calcium orthophosphate during calcification, which then darkens with exposure to light. With minocycline, however, the staining occurs after eruption in previously normal-colored, fully mineralized adult teeth. For example, adult-onset tooth discoloration coincident with minocycUne administration occurred in four of 72 patients (7). 

Co-administration of tetracyclines with antacids or other drugs containing divalent or trivalent cations, such as calcium, magnesium, or iron, is contraindicated. Tetracyclines form complexes with such cations, which are very poorly or not at all absorbed (75,174,175). 

The complexing of tetracyclines with calcium poses a problem in paediatric medicine. Discoloration of teeth results from the formation of a coloured complex with the calcium in the teeth the deposition of drug in the hones of growing hahies can lead to problems in bone formation. Table 10.4 reveals that there is no correlation between the binding capacity of a tetracycline with iron and that with calcium, suggesting different modes of complexation. The in vitro data are simpler to interpret the semm levels are the... 

Chemical interactions in the gastrointestinal tract between nutrients and drugs may considerably reduce the absorption of some drugs calcium ions from dairy products form insoluble and therefore nonabsorbable complexes with the antibiotic tetracycline. On the other hand, certain drugs are irritants to the gastrointestinal tract (nonsteroidal antiinflammatory drugs and potassium chloride tablets) and must be ingested with food. 

Tetracycline forms insoluble complexes with calcium ions. Absorption of these antibiotics is substantially reduced if they are taken with milk, certain food or other sources of calcium such as some antacids. In the past, the incorporation of dicalcium phosphate as a filler in tetracycline dosage forms also reduced its bioavailability. 

An example is the increase in lipid solubility achieved by chemical modification by tetracycline to give the derivative doxycycline. Doxycycline (Vibramycin) is more efficiently absorbed from the intestine than is tetracycline, partly because of better lipid solubility and partly because of a decreased tendency to form poorly soluble complexes with calcium. 

An active substance, although initially released from its dosage form (and dissolved), may become unavailable for absorption due to reactimis with other medicines or food components [4]. An example is the formation of insoluble complexes of tetracycline with calcium or aluminium ions from antacids or milk products. Interaction (chelation or binding) with iron ions leads to a reduced absorption for a variety of active substances such as doxycycline, penicillamine, methyldopa and ciprofloxacin. The absorption of active substances showing pH-dependent dissolution behaviour may be influenced by medicines that influence the gastric pH, such as H2-antagonists, proton pump inhibitors and antacids. Antimycotic active substances such as ketoconazole or itraconazole dissolve better in acidic fluids. Therefore their bioavailability may be increased by the concomitant use of an acidic drink like cola, whereas the concomitant use of antacids or proton pump inhibitors is likely to reduce the bioavailability. Concomitant use of milk may increase the dissolution of acidic active substances, whereas fats from food may increase the bioavailability of lipophilic active substances like albendazole and griseofulvin. 

Tetracyclines and fluoroquinolones form strong complexes with bivalent ions like calcium. Therefore, EDTA was added during milk extraction and EDTA-modified silica gel was selected as a layer material offering the best separation (free of tailing) of the target compounds and a signihcant fluorescence enhancement effect for a low limit of detection. The selected solvent system provided the complete separation of the seven antibiotics (Eigure 10.4), when a 10% EDTA solution for the layer modification was verified as optimal for the best separation of TCs and EQs [6]. 

Antibiotics—The tetracycline types of these drugs may form insoluble, unabsorbable complexes with such essential minerals as calcium, iron, and magnesium. 

Reduced absorption due to complex formation or other interactions between drugs and intestinal components leading to poor absorption has been described in a few cases. One example is the precipitation of cationic drugs as very poorly-soluble salts with bile acids, which has been reported for several compounds [62], Another well-known example is the complex formation between tetracycline together with calcium due to chelation after administration of the drug together... 

The absorption of tetracycline administered orally is variable and depend upon the type of tetracycline used. The tetracycline form insoluble complexes i.e. chelation with calcium, magnesium, milk and antacids reduce their absorption. Administration of iron also interferes with the absorption of tetracycline. Doxycycline is rapidly and virtually completely absorbed after oral administration and its absorption is not affected by presence of food or milk. 

Tetracyclines and Metals. Tetracyclines can combine with metal ions, such as calcium, magnesium, aluminum, and iron, in the GI tract to form complexes that are poorly absorbed. Thus, the simultaneous administration of certain drugs (e.g., antacids, iron preparations, products containing calcium salts) by patients on tetracycline therapy could result in a significant decrease in the amount of antibiotic absorbed. When two drugs are recognized as having a potential to interact, there is sometimes a tendency to believe that one of them should be discontinued. In the case of the tetracycline antacid interactions, problems can be... 

In the presence of moisture, calcium salts may be incompatible with amines, amino acids, peptides, and proteins, which may form complexes. Calcium salts will interfere with the bioavailability of tetracycline antibiotics. It is also anticipated that calcium sulfate would be incompatible with indomethacin, aspirin, aspartame, ampicillin, cephalexin, and eryth-romycin " " since these materials are incompatible with other calcium salts. 

Calcium absorption is reduced by high pH complex-ing agents such as oxalate, phytate, free fatty acids, and phosphate and shortened transit times. These factors are probably of clinical importance only when associated with vitamin D deficiency, marginal calcium intake, or malabsorption disorders. Absorption is also reduced by increased intake of protein, fat, and plant fiber increasing age stress chronic alcoholism immobilization (e.g., prolonged hospitalization) and drugs such as tetracycline, thyroid extract, diuretics, and aluminum-containing antacids. 

Tetracyclines This very successful class of antibacterials act selectively on the bacterial ribosome inhibiting protein synthesis. They do not bind with mammalian ribosomes in the cytoplasm and, therefore, do not have a direct effect on the patient s metabolism. Like any drug, they are not free of potentially harmful side effects. They complex calcium and can interfere with development of the permanent teeth prior to their erupting through the gums As with the sulfonamides, this class... 

But calcium citrate, which is more soluble at a neutral pH, may still be the preferable form for those with compromised levels of stomach acid. Phytates and oxalic acid, found in spinach, rhubarb, collard greens, sweet potatoes and beans bind calcium, creating insoluble complexes that cannot be absorbed. Calcium can also decrease the absorption of several medications including quinolone antibiotics, tetracycline, and thyroid replacement medication. 

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