Tetracyclines drug-metal chelates

The tetracyclines have an avidity for divalent metals similar to that of glycine (III) but they have a greater affinity for the triva-lent metals with which they form 3 1 drug-metal chelates. Therapeutically active tetracyclines form 2 1 complexes with cupric, nickel and zinc ions while inactive analogues form only 1 I complexes. 

These antibiotics are partially absorbed from the stomach and upper gastrointestinal tract. Food impairs absorption of all tetracyclines except doxycycline and minocycline. Absorption of doxycycline and minocy-cbne is improved with food. Since the tetracyclines form insoluble chelates with calcium (such as are found in many antacids), magnesium, and other metal ions, their simultaneous administration with milk (calcium), magnesium hydroxide, aluminum hydroxide, or iron will interfere with absorption. Because some of the tetracyclines are not completely absorbed, any drug remaining in the intestine may inhibit sensitive intestinal microorganisms and alter the normal intestinal flora. 

Metabolism studies in dogs and rats with radiolabeled tetracycline showed that with the exception of metal-chelate formation, tetracycline was chemically unaltered by the rat (247). Organ extracts from dosed animals were not found to contain metabolic products of tetracycline. Dog urine also contained unchanged drug, indicating that metabolic transformation of tetracycline had not occurred. 

Tetracyclines have the tendency to form chelates with bivalent metal ions. As a consequence of their affinity to calcium, tetracyclines tend to accumulate in the bones of treated animals. Although their chelates with calcium show considerable stability, tetracyclines can be extracted from bones containing these drugs and, therefore, may be present in soups and meals when bones from treated animals are cooked (80, 81). The extractability of chlortetracycline from bone tissue is strongly pH-dependent, being higher at low pH values. This can be easily explained by the dependence of the dissociation constant of the chelate from the pH value. 

Tetracycline Tetracycline injections have an acid pH. Incompatibility may reasonably be expected with alkaline preparations or with drugs unstable at low pH. Care should be taken when administering tetracyclines, since chelation takes place with metal ions. Tetracyclines interact with inorganic metal ions. They should not be used with drugs that cause hepatotoxicity and nephrotoxicity (e.g., digoxin, theophylline, ergot alkaloids, methotrexate, oral contraceptives, and penicillins). 

Conventional reversed-phase LC has been the most common choice in veterinary drug analysis. However, some veterinary drugs exhibit properties that make difficult their separation with traditional C18 columns. That is the case of many antibacterials (e.g., tetracyclines, aminoglycosides, macrolides, and fluoroquinolones) that either form chelates with metallic column impurities form chelates on the column with metallic impurities or imcovered silanolic residues or are poorly retained on the C18 columns because of their high polarity (e.g., aminoglycosides). In other situations, the separation of isomeric and tautomeric forms (e.g., tetracyclines and glucocorticoids) is possible by a careful optimization of the chromatographic conditions. 

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